key: cord-018430-u3k8pds6
authors: Mason, Jay W.; Trehan, Sanjeev; Renlund, Dale G.
title: Myocarditis
date: 2007
journal: Cardiovascular Medicine
DOI: 10.1007/978-1-84628-715-2_62
sha: 
doc_id: 18430
cord_uid: u3k8pds6

Viruses are the most common cause of myocarditis in economically advanced countries. Enteroviruses and adenoviruses are the most common etiologic agents. Viral myocarditis is a triphasic process. Phase 1 is the period of active viral replication in the myocardium during which the symptoms of myocardial damage range from none to cardiogenic shock. If the disease process continues, it enters phase 2, which is characterized by autoimmunity triggered by viral and myocardial proteins. Heart failure often appears for the first time in phase 2. Phase 3, dilated cardiomyopathy, is the end result in some patients. Diagnostic procedures and treatment should be tailored to the phase of disease. Viral myocarditis is a significant cause of dilated cardiomyopathy, as proved by the frequent presence of viral genomic material in the myocardium, and by improvement in ventricular function by immunomodulatory therapy. Myocarditis of any etiology usually presents with heart failure, but the second most common presentation is ventricular arrhythmia. As a result, myocarditis is one of the most common causes of sudden death in young people and others without preexisting structural heart disease. Myocarditis can be definitively diagnosed by endomyocardial biopsy. However, it is clear that existing criteria for the histologic diagnosis need to be refined, and that a variety of molecular markers in the myocardium and the circulation can be used to establish the diagnosis. Treatment of myocarditis has been generally disappointing. Accurate staging of the disease will undoubtedly improve treatment in the future. It is clear that immunosuppression and immunomodulation are effective in some patients, especially during phase 2, but may not be as useful in phases 1 and 3. Since myocarditis is often selflimited, bridging and recovery therapy with circulatory assistance may be effective. Prevention by immunization or receptor blocking strategies is under development. Giant cell myocarditis is an unusually fulminant form of the disease that progresses rapidly to heart failure or sudden death. Rapid onset of disease in young people, especially those with other autoimmune manifestations, accompanied by heart failure or ventricular arrhythmias, suggests giant cell myocarditis. Peripartum cardiomyopathy in economically developed countries is usually the result of myocarditis.

Jay W. Mason, Sanjeev Trehan, and Dale G. Renlund

• Viruses are the most common cause of myocarditis in economically advanced countries. • Enteroviruses and adenoviruses are the most common etiologic agents. • Viral myocarditis is a triphasic process. Phase 1 is the period of active viral replication in the myocardium during which the symptoms of myocardial damage range from none to cardiogenic shock. If the disease process continues, it enters phase 2, which is characterized by autoimmunity triggered by viral and myocardial proteins. Heart failure often appears for the first time in phase 2. Phase 3, dilated cardiomyopathy, is the end result in some patients. Diagnostic procedures and treatment should be tailored to the phase of disease. • Viral myocarditis is a significant cause of dilated cardiomyopathy, as proved by the frequent presence of viral genomic material in the myocardium, and by improvement in ventricular function by immunomodulatory therapy. • Myocarditis of any etiology usually presents with heart failure, but the second most common presentation is ventricular arrhythmia. As a result, myocarditis is one of the most common causes of sudden death in young people and others without preexisting structural heart disease. • Myocarditis can be definitively diagnosed by endomyocardial biopsy. However, it is clear that existing criteria for the histologic diagnosis need to be refined, and that a variety of molecular markers in the myocardium and the circulation can be used to establish the diagnosis. • Treatment of myocarditis has been generally disappointing. Accurate staging of the disease will undoubtedly improve treatment in the future. It is clear that immunosuppression and immunomodulation are effective in some patients, especially during phase 2, but may not be as useful in phases 1 and 3. Since myocarditis is often selflimited, bridging and recovery therapy with circulatory assistance may be effective. Prevention by immunization or receptor blocking strategies is under development.

• Giant cell myocarditis is an unusually fulminant form of the disease that progresses rapidly to heart failure or sudden death. Rapid onset of disease in young people, especially those with other autoimmune manifestations, accompanied by heart failure or ventricular arrhythmias, suggests giant cell myocarditis. • Peripartum cardiomyopathy in economically developed countries is usually the result of myocarditis.

The difficulty of diagnosing and treating myocarditis was recognized by Senac 1 in 1772: "The inflammation of the heart is difficult to diagnose and when we have diagnosed it, can we then treat it better?" After Sobernheim 2 in 1837 defined myocarditis as any inflammation or degeneration of the heart, the term myocarditis was used for nonvalvular myocardial diseases, including ischemic and hypertensive cardiomyopathies. Nearly a century later, White 3 suggested that the term myocarditis be restricted to "true inflammation of the myocardium." The last half-century has seen the development of endomyocardial biopsy techniques, histologic criteria, and serologic methods to diagnose myocarditis. As our knowledge of the immunopathologic mechanisms evolves, new therapeutic strategies are developing. The World Health Organization/International Society and Federation of Cardiology Task Force on Cardiomyopathies 4 classified cardiomyopathies whenever possible by etiologic/pathogenetic factors. This classification recognizes chronic viral, postinfectious autoimmune, and primary autoimmune forms of dilated cardiomyopathy (DCM). The classification states that "myocarditis is diagnosed by established histological, immunological and immunohistochemical criteria." The Dallas criteria 5 provide consensus-derived histologic criteria: "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of ischemic damage associated with coronary artery disease." However, many have speculated that less pronounced histologic abnormalities may be present and that additional molecular, immunologic, and immunohistochemical diagnostic criteria can be used productively. [6] [7] [8] [9] [10] [11] Myocarditis, irrespective of the etiopathologic factors, remains an inflammatory cardiomyopathy associated with cardiac dysfunction.

A wide variety of infectious and noninfectious causes are associated with myocarditis (Tables 59.1 to 59.3) . Several epidemiologic observations linking these agents with myocarditis have been corroborated by serologic, polymerase chain reaction (PCR), or in situ hybridization methods. The incidence of infectious myocarditis in the general population is largely unknown. In a prospective study 12 over several years, in a predefined subpopulation, an incidence of 0.02% was found. These cases were confirmed by myocardial enzyme leak and characteristic electrocardiographic (ECG) changes. 12 The ECG abnormalities suggesting asymptomatic myocardial involvement, in the absence of enzyme release, have been noted in 1.2% of military conscripts during the course of other acute infectious diseases. 13 During an epidemic of influenza A, the incidence rose to 7.7%. 14 In a prospective trial of 2310 consecutive patients admitted to a large infectious disease hospital in Sweden, 8% showed ECG abnormalities suggestive of myocarditis. 15 Approximately 5% of a virus-infected population may experience symptoms or findings suggestive of cardiac involvement. The incidence of myocarditis associated with nonviral infections is even more difficult to estimate. Although the list of possible etiologic agents is large, the enteroviruses, specifically coxsackievirus B, over decades have been the most commonly identified etiologic agents of inflammatory cardiomyopathy. Among healthy active adults, at least 50% have detectable serum antibodies indicating prior infection with coxsackievirus B. 16, 17 The World Health Organization has surveyed viral infections related to cardiovascular disease globally. In a 10year period from 1975 to 1985, coxsackievirus B had the highest incidence of cardiovascular disease (34.6 cases per 1000 population), followed by influenza B (17.4 cases), influenza A (11.7 cases), coxsackievirus A (9.1 cases), and cytomegalovirus (CMV) (8.0 cases). 18 The predominance of enteroviruses among myocarditisassociated agents has been substantiated by several laboratory and clinical studies. [19] [20] [21] Using serologic methods, Vikerfors and associates 19 reported that nearly 50% of consecutively studied myocarditis patients had enterovirus immunoglobulin IgM. Frisk and coworkers 20 found a similar incidence of coxsackievirus B IgM antibodies by reverse herpes simplex in two, and CMV in one patient. The control group did not demonstrate any viral genome sequences. Just as the incidence of specific viral infections varies over time, so should the relative proportion of agents responsible for myocarditis. In a recent study, Bowles and colleagues 22 supported the observation by Martin and coworkers 21 that adenovirus is the most common agent associated with myocarditis in children, but they also found that adenoviruses predominated over enteroviruses in adults. Figure 59 .1 shows the dominant role of adenoviruses and enteroviruses in myocarditis. Note that parvovirus was detected in young people. Parvovirus B-19 has recently been identified as a cause of myocarditis and, in some regions, it has been found in adults as well as children. [23] [24] [25] [26] [27] These differences between previous and newer studies are due, at least in part, to geographical and temporal variation in the incidence of specific viral infections.

Cytomegalovirus is a recognized cause of acute infectious myocarditis, although it is rare in healthy individuals. 28 , 29 Maisch and associates 30 demonstrated, using in situ hybridization techniques, CMV-specific nucleotide sequences in 15% of patients with acute myopericarditis. Certainly in transplant recipients, CMV infection is fairly common and has been reported to affect the transplanted heart. 31, 32 Hepatitis C virus infection is frequently noted in patients with DCM, 33 and hepatitis C virus RNA has also been recovered from lymphocytes infiltrating the myocardium in chronic active myocarditis. 34 Matsumori and colleagues 35, 36 found a high incidence of hepatitis C viral genomic material in a wide variety of cardiac disorders in Japan.

Myocarditis is a well-recognized complication of Corynebacterium diphtheriae infection, although this is now rare in the Western world. 37 Myocardial dysfunction is also seen in association with Salmonella septicemia, although it is rarely clinically severe. 38, 39 Myocardial dysfunction is primarily related to the toxemia of the severe infection, which is also observed in meningococcal and nonrheumatic streptococcal infections.

Perhaps the best-recognized bacterial agent thought to be responsible for myocarditis is the β-hemolytic streptococcus that causes rheumatic fever. Fortunately, rheumatic fever is seen in the Western world with only a low frequency of sporadic cases in regional clusters. The incidence in the United States is less than 2 per 100,000, but in the developing world, rheumatic heart disease continues to be the leading cause of cardiac hospitalization in the 5-to 25-year-old age group. 40 Although the inflammatory component of rheumatic carditis is largely restricted to the valves, it has been believed to cause myocardial dysfunction.

Myocarditis is a well-documented complication of Borrelia burgdorferi infection (Lyme disease) and is reported in up to 8% of cases. Cardiac involvement is often characterized by the development of atrioventricular (AV) block and rarely progresses to left ventricular dysfunction and cardiomegaly. 41 Mycoplasma pneumoniae infection has also been associated with myocarditis. Lewes and coworkers 42 demonstrated asymptomatic myocardial involvement as documented by ECG changes in a third of the cases with acute Mycoplasma infection. Six percent of military conscripts with clinical myocarditis were found to have active M. pneumoniae infection. 43 Chlamydia infections have also been associated with myocarditis, especially among small children, often having fatal outcomes. 44 C. pneumoniae infection has also been noted in a few cases of mild myocarditis 45 and has been found with respiratory infection associated with myocarditis, resulting in sudden death in a young athlete. 46 Chlamydia psittaci infection may be associated with myocarditis in 5% to 15% of those affected, usually with minimal clinical signs or symptoms. 44 Pericarditis is more frequent and likely to cause cardiac morbidity with ornithosis. 47 Other Causative Infectious Agents Rickettsial infections, like Rocky Mountain spotted fever and scrub typhus, are frequently accompanied by myocardial involvement, although vasculitis is more prominent with these infections. 48 Q fever may also be associated with myocarditis. 49 Trypanosoma cruzi is a well-recognized cause of myocarditis and cardiomyopathy in South America (Chagas' disease). 50 Toxoplasma gondii poses a significant problem among cardiac transplant recipients because a large number of the recipients lack antibodies against this agent, which may cause myocarditis. 51 Toxoplasmosis also poses a major threat to patients with AIDS. Myocarditis has frequently been seen in human immunodeficiency virus (HIV)-infected populations with or without concomitant Toxoplasma infection. 52, 53 In two autopsy studies of patients with AIDS, myocarditis was found in almost half of the cases; in another study, 54% of 102 prospectively studied patients with AIDS had echocardiographic evidence of myocardial dysfunction. 54, 55 Myocarditis may also occur in patients with AIDS as a result of T-cell restitution after antiviral therapy. 56 Myocarditis can also be seen with parasitic infections such as Trichinella spiralis, which has an affinity for striated muscle, including the heart. 57 Other Noninfectious Causes Noninfectious causes of myocarditis include druginduced hypersensitivity, 58-89 direct toxicity of specific pharmaceutical agents, 77, [90] [91] [92] and systemic collagen vascular disorders. [93] [94] [95] [96] [97] [98] [99] [100] Eosinophilic myocarditis [101] [102] [103] [104] and giant cell myocarditis (GCM) [105] [106] [107] [108] [109] [110] [111] are distinct forms of inflammatory myocarditis of uncertain etiology.

Microorganisms are rarely isolated or demonstrated in heart muscle; hence, identification of a specific infectious etiologic agent depends on recognition of its systemic manifestations. Once specific noninfectious and nonviral infectious agents are excluded, myocarditis is often assumed to be of viral etiology. Although definitive serologic evidence of viral infection can be obtained in many patients, it is absent in the majority of patients with presumed myocarditis. A significant number of cases of myocarditis is due to autoimmune phenomena either induced by a viral infection or resulting from systemic autoimmune disease. Since the establishment of definitive etiologic diagnoses is ambiguous, the terms viral myocarditis, idiopathic myocarditis, lymphocytic myocarditis, autoimmune myocarditis, and interstitial myocarditis are frequently used interchangeably.

The pathophysiologic mechanisms of myocarditis in humans are not fully understood. Clearly, multiple mechanisms exist, including direct infection by viruses, bacteria, and other organisms; noninfectious causes, such as toxins and drug hypersensitivity; and parainfectious etiologies, resulting from the immune response to infection. Most cases of overt heart failure due to myocarditis in North America, Europe, and Japan are thought to arise from the latter type of mechanism, during and after viral infection of the heart. A triphasic disease process is observed 112, 113 (Fig. 59.2A ). In the first phase, active viral infection of the myocardium results in a variable extent of muscle damage, which often may not be clinically apparent. Phase 2 develops in an unknown proportion of infected individuals after partial or complete resolution of active infection and is characterized by further myocardial damage, both by ongoing immune activation and by newly developed autoimmune activity. A small proportion of patients develops dilated cardiomyopathy, the third phase of disease, resulting from the cumulative damage caused by infection, immunity, and autoimmunity. During this phase, a considerable body of evidence suggests that the immune and autoimmune processes persist, in part as a result of viral persistence. 114 Figure 59 .2B depicts the three roles virus may play in bringing about dilatation and chronic heart failure. After the initial injury that occurs during active viral replication, latent, nonreplicating viruses can still alter myocyte function through viral genomic expression. 115 Even if the virus is completely eliminated and the immune response ceases, through the various mechanisms of adverse remodeling, the cardiomyopathy may progress inexorably.

The most widely accepted models for the study of human myocarditis are those of enteroviral myocarditis induced by coxsackievirus B3 (CVB3) and the encephalomyocarditis virus. 116 Induction of chronic murine myocarditis by CVB3 requires the virus to have a cardiovirulence capacity and murine strains of certain genetic background. 117, 118 Infection of syngeneic weanling mice with CVB3 results in brief cardiac infection lasting about a week, beyond which the virus cannot be cultured. However, viral RNA persists for several months after the initial infection. 119, 120 Several mechanisms have been hypothesized to explain the initiation of chronic inflammatory response in myocytes by the viral infection: 60. 134 Although antibodies to these antigens are frequently identified in association with myocarditis, the clinical significance and causal relationship are yet unresolved. Cytotoxic lymphocytes (CTLs) from mice with CVB3induced myocarditis possess the ability in vitro to recognize and kill neonatal myocytes, fibroblasts, and endothelial cells infected with the same strain of the virus, 135 suggesting that the recognition of a novel tissue antigen is induced by the infection. Cross-reactive, concurrent recognition of unrelated cardiac epitopes also occurs because CTLs also lyse uninfected myocytes in vitro. 136 The production of perforin, a pore-forming protein, has been proposed as one of the mechanisms for the cytolysis induced by lymphocytes. Perforins, when inserted into myocyte membrane, induce a lethal augmentation in cell permeability that results in cellular edema and death. 137 Perforin-independent mechanisms have also been proposed, including a Fas (CD95/Apol)-based inositol-1,4,5-triphosphate-mediated cytolysis that can be demonstrated in perforin-deficient gene-knockout mice. 138 Coxsackievirus-infected mice also develop additional immune sensitization to cardiac heavy chain myosin, possibly owing to the release of the sequestered myosin antigens from the virus-damaged cells. Immunization of mice with the heavy chain myosin and an adjuvant produces a histomorphologically similar picture to CVB3-induced myocarditis. Adoptive transfer of splenocytes can also produce experimental autoimmune myocarditis after myocardial infarction in syngeneic rats. The sensitized lymphocytes when transferred to normal rats cause cardiac-specific cellular infiltration with accompanying myocyte necrosis. 139 The genetic susceptibility, kinetics, and cellular composition of the infiltrates in these models are similar and suggest the role of endogenous antigens as an epitope for the inflammatory response. 140

The pathways and cellular participants in the immunopathogenesis of experimental viral myocarditis are well recognized. The replicating viral particles can be readily identified in cardiac myocytes within a few hours of inoculation of CVB3 into mice. 141,142 The viral particles reach a numerical peak in 3 to 4 days, and usually at 7 to 10 days, they are no longer detectable. 143 The inflammatory infiltrate is detectable by day 5 and reaches a plateau by days 7 to 10. The early inflammatory infiltrate consists of lymphocytes, macrophages, neutrophils, natural killer cells, and the associated cytokines and humoral effectors. [144] [145] [146] The natural killer cells are the first to appear and are detected in the activated state in 3 to 4 days. These cells are capable of lysing virusinfected cells in vitro. 145 The T lymphocytes and macrophages follow the natural killer cells in the temporal sequence and become the predominant cells infiltrating the myocardium in 7 to 10 days. Although CVB3 replicates readily in myocytes in vitro, the cells are resistant to lysis in comparison with other cultured cell lines. Direct myocytolysis appears to play a minimal role in cell lines derived from normal mice. 147 The immunodeficient severe combined immunodeficiency (SCID) mouse model has provided valuable insight into the early immune activity in response to the viral infection. The SCID mice lack mature T-and B-lymphocyte function and develop extensive myocardial necrosis with pleomorphic infiltrates, rapid viral proliferation, and profound virus-associated myocytolysis when inoculated with CVB3. 148 The macrophage and natural killer cell activity is unaffected in the SCID mouse model and may participate in the myocytolytic activity, although direct viral myocytolysis predominates. Pharmacologically immunosuppressed mice demonstrate similar characteristics, with higher viral loads, delayed clearance, and extensive myocyte necrosis, although direct viral myocytolysis is not frequent in immunocompetent mice. 143,147,149-151 Even noncardiovirulent strains may have sufficient time to replicate and transform into quasicardiovirulent species in the absence of a functional antiviral immune response, which can then result in fatal myocarditis. 152 This may also explain the clinical observation that many severe and fatal cases of myocarditis develop in young children with immature and incompletely developed immune systems. 153 Virus-specific CTLs play a major role in the inflammatory response to viral infection of the myocytc. 143,151 The inflammatory response can be diminished significantly by T-lymphocyte depletion with either antithymocyte globulin or thymectomy and irradiation. 142,154 The CTLs must recognize the foreign antigen in association with the syngeneic major histocompatibility complex (MHC) class I antigen that is found on immune-derived cells. The CVB3-infected cells can readily express MHC class I antigens. 155 The MHC class I molecules provide peptide-binding sites that evoke effector responses on recognition of the foreign peptide by the antigenspecific receptors of the T lymphocyte. 156 However, Tlymphocyte depletion and specific immunosuppression using cyclosporine have varying effects, depending on the murine model, the virus, and the time of therapy, and are not uniformly beneficial. [157] [158] [159] The virus can no longer be cultured from cells after 7 to 10 days; however, areas of inflammatory infiltrate and myocyte necrosis do demonstrate persistence of viral RNA, and the virus-specific CTLs may continue to see these as immunologic targets and, hence, perpetuate the myocyte damage. 160 The infected myocyte can still remain a target for the CTLs, even if the viral antigens are cleared, owing to expression of "neoantigens" either induced by the virus or unsequestered due to the injury. 161,162 Even nonviral antigens on infected myocytes can react with CTLs, such as those induced by actinomycin D, 162 and new glycoproteins have been identified on the surface of CVB3-infected cells that can be recognized by CTLs from other syngeneic-infected mice. 163 Recent observations suggest that co-stimulatory molecules B7-1, B7-2, and CD-40 may be expressed on myocytes in patients with myocarditis and may make the myocytes into antigen-presenting cells for CTLs and natural killer cells, thereby playing an important role in the direct myocardial damage by these lytic cells. 164 

Another mechanism for ongoing myocyte damage is the antibody-mediated autoimmune response. Since the majority of the proteins identified as cardiac autoantigens are intracellular, it is unclear how these antibodies could harm normal intact myocytes. Several mechanisms are proposed. One suggests that after the antibody response is initiated, the circulating antibodies to intracellular antigens crossreact with the native membrane cardiac tissue proteins. Thus, after a small number of myocytes are damaged by the viral infection and release intracellular antigens, the resulting antibody response may affect normal myocytes, leading to global myocardial dysfunction. This hypothesis is supported by the demonstration of a number of cross-reacting antibodies. [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] Also, the antibodies against the intracellular mitochondrial adenine nucleotide transferase protein cross-react with the myocyte sarcolemmal calcium ion channel protein, and binding of these channels can physiologically alter the metabolism and contractile function of the myocyte. 165 Another theory holds that CTLs and antibodies target uninfected myocytes by recognition of self-antigens that were previously sequestered from immune surveillance. The processing and presentation of the self-immunogenic peptides complexed with the MHC is a prerequisite for this hypothesis. Normal human cardiac myocytes do not express detectable levels of MHC class II antigens, and their constitutive expression of MHC class I molecules remains controversial. 166 A significant increase in the expression of MHC class I and class II antigens by the myocytes has been demonstrated in association with myocardial inflammation, such as that seen with viral myocarditis or transplant rejection. [167] [168] [169] The increased MHC expression has also been demonstrated in endomyocardial biopsy specimens from patients with idiopathic DCM and myocarditis, [170] [171] [172] and immune regulatory dysfunction may have a genetic predisposition. 173 There is also evidence for aberrant expression of intracellular antigens, such as adenine nucleotide translocator (ANT) and branched-chain α-keto acid dehydrogenase (BCKD), on the surface of the myocytes. 172 The formation of antiidiotypic antibodies is an additional mechanism of immune regulation in which an antibody is formed to the idiotypic determinants (antigen recognition site) of the primary antibody. The antiidiotypic antibody may cross-react with unoccupied viral receptor sites on uninfected myocytes. This phenomenon has been reported with the reovirus, polyomavirus, and coxsackievirus B models of myocarditis. [174] [175] [176] The passive transfer of antiidiotypic B cells from a CVB3 myocarditic mouse to a syngeneic mouse can cause nonviral myocarditis. 177 

The presence of a complex, cytokine-rich microenvironment is suggested by the heterogeneous inflammatory cell populations in the hearts of infected mice. The cytokines perform myriad immunomodulatory functions, including regulation of antibody production, preservation of self-tolerance, 178, 179 conscription of ancillary cells in the inflammatory milieu, 180, 181 and maintenance of clonal expansion of CTLs. 182, 183 Certain cytokines regulate the collagenogenic and collagenolytic activity of fibroblasts. 184 Although mounting evidence supports the negative inotropic effects or the blunting of catecholamine response in myocytes exposed to various cytokines, there is no direct evidence to suggest that the cytokines are directly responsible for myocytolysis. 185 In an in vitro model, Barry 185 demonstrated that high concentrations of interleukin (IL)-1, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and IL-4 have no effect on myocyte survival over 24 hours, whereas the CTLs from a mixed lymphocyte reaction cause virtually 100% killing.

Gulick and colleagues 186 demonstrated that cultured neonatal myocytes, when exposed to macrophage-derived IL-1 and TNF-α, have reduced levels of cyclic adenosine monophosphate and have a reduced inotropic response to catecholamines. The mechanism for decreased responsiveness to catecholamines is believed to be modulated by increases in nitric oxide production mediated by increased inducible nitric oxide synthase (iNOS) activity, and the blunting of the catecholamine response can be inhibited by the L-arginine analogue N G -monomethyl-l-arginine (l-NMMA). 187 The decreased contractile response of cardiac myocytes to β-adrenergic agonists following induction of iNOS also requires the presence of insulin and the co-induction of enzymes responsible for the production of tetrahydrobiopterin, a cofactor for nitric oxide synthase. 188 The role of iNOS remains controversial because increased expression of iNOS mRNA and that of other proinflammatory cytokines is evident and is associated with contractile dysfunction. 189 There is evidence to support the idea that iNOS induction is crucial for the host response to CVB3 infection, and iNOS-deficient mice have significantly increased viral loads with extensive myocardial damage. 190 Inhibition of iNOS through suppression of nuclear factor (NF)-κB induction has recently been shown to prevent encephalomyocarditis virus myocarditis. 191 Other investigators have suggested that inflammatory cytokines may have direct negative inotropic effects, independent of the responsiveness to the β-adrenergic agonists. High doses of IL-2 during chemotherapy have been reported to result in depression of myocardial function. 89 Exposure of cardiac myocytes to endotoxin results in increased nitric oxide production and direct depression of contractility owing to increased levels of cyclic guanosine monophosphate. 192 Further, TNF-α may induce direct negative inotropic effects by decreasing the Ca 2+ transient, with no change in the l-type Ca 2+ current and independent of nitric oxide synthesis. 193 Although the extent to which cytokines cause direct negative inotropic effects or attenuation of endogenous β-adrenergic agonist activity remains unclear, they do produce myocyte dysfunction and cardiac decompensation. Transgenic mice with overexpression of TNF-α develop biventricular dilatation and cardiac failure, resulting in premature death. Pathologic specimens from these mice reveal globular dilated hearts and transmural myocarditis with myocyte apoptosis. 194 Increased levels of intracellular adhesion molecule (ICAM-1), IL-1α, IL-1β, TNF-α, and macrophage-stimulating factor have been demonstrated in patients with myocarditis and idiopathic DCM. 195, 196 Furthermore, the susceptibility of mice in the CVB3 myocarditis model can be increased by pretreatment with these cytokines. 197 Transforming growth factor-β is identifiable by immunohistochemistry in the prenecrotic regions of infiltrates in the murine myocardium and decreases when the macrophages and fibroblasts migrate to the necrotic foci. These growth factors may be responsible for recruitment of the immunologic effectors and may directly affect cardiac function. 198 An intriguing feature of cytokine activity remains their possible role in the secondary development of myocyte hypertrophy and interstitial fibrosis, characteristic of dilated cardiomyopathy. 199 Among animals with different forms of viral myocarditis associated with similar intensity of initial myocyte necrosis, only those animals with persistent inflammation develop interstitial fibrosis, reflected by fibroblast proliferation and an increase in the extracellular matrix. Myocardial fibrosis correlates well with the presence of T lymphocytes and macrophages, which in their activated state release fibrogenic cytokines such as fibroblast growth factor and transforming growth factor-β. 200 Matrix metalloproteinases (MMPs), and their inhibitors, are thought to play a critical role in the process of myocardial remodeling. Some of the cytokines elaborated during the course of viral myocarditis, such as TNF-α, disturb the balance between MMPs and their inhibitors by increasing MMP, leading to failure of collagen cross-linking and worsened ventricular function ( Fig. 59.3 ). 201 This pathophysiology may present opportunities for prevention of the development of dilated cardiomyopathy resulting from myocarditis.

Extracardial reservoir secondary transfer to the target organ (e.g., heart) Viral replication in the target organ viral protein expression 

Lymphocytic myocarditis models in animals have conclusively demonstrated the association of viral infection and myocarditis. This association clearly exists in humans, but the proportion of cases that can be accounted for by viral infection is not known. The myocardial damage in murine models of viral myocarditis occurs in two distinct phases: an early phase of direct viral cytotoxicity in which virusspecific T-lymphocyte-and antibody-mediated cytotoxicity predominate; and a late or chronic phase in which the persistent viral genome, reactive CTLs, autoantibodies, cytokines, and microvascular damage mediate myocyte damage and dysfunction. The hypothetical mechanisms of virusinduced autoimmune heart disease are presented in Figures 59.2 to 59.4. The recognition that immune responses to specific viruses are consequential in the development of myocyte injury has led to exhaustive research to exploit the possibility of designing immunomodulatory and antiviral therapies. The pretreatment of mice with inactivated virus vaccine prevents the manifestations of encephalomyocarditis virus myocarditis. 202 The administration of antiviral therapies reduces the viral load and attenuates the histologic findings of myocarditis. 203, 204 The antiviral response can be augmented by IFN-α or the exogenous administration of IL-6. 205, 206 Recombinant murine IFN-γ has also been demonstrated to improve the prognosis of acute murine myocarditis caused by encephalomyocarditis virus by suppressing replication. 207 The murine model has also been the subject of intensive study with clinically applied immunosuppressants, such as corticosteroids, 208 nonsteroidal antiinflammatory agents, 209, 210 and cyclophosphamide, 211 all of which have demonstrated deleterious effects when given in the acute viremic phase. Cyclosporine, when administered in the early viremic phase, worsens myocardial injury but, in the late immune phase, has a beneficial effect. 157,158, 212 Similar results have been reported with tacrolimus, 213 and survival improves significantly when immunosuppressants such as cyclosporine, azathioprine, and 15-deoxyspergualin are used in adjunct to immunomodulators, such as IFN-α. 214 Antibodies to TNF-α have been demonstrated to improve survival and reduce myocardial injury. 215 Cytokine inhibitors have had promising results in animal models, but human clinical trials have been inconsistent. Vesnarinone, a phosphodiesterase III inhibitor, has demonstrated beneficial hemodynamic effects and inhibits the production of TNF-α and favorably modulates induction of iNOS. 216 Amlodipine has also been shown to increase survival of mice with viral myocarditis by inhibiting expression of iNOS and production of nitric oxide in vivo and in vitro. 217 

The diversity of immunopathogenetic mechanisms and variability in the severity of observed disease in the murine model are only a preview to the potpourri of clinical manifestations of myocarditis in humans. The presentation of unexplained progressive cardiac dysfunction or ventricular arrhythmias should lead to the suspicion of myocarditis, especially when routine cardiac diagnostic studies do not reveal an etiology. The history of an antecedent viral infection or prodrome is often sought but seldom reported and rarely confirmed by convalescent serologies. The presence of mild elevation of creatine kinase MB isoenzyme (CK-MB) or troponin, leukocytosis, or ECG changes may further underscore the possibility of myocarditis.

Most patients with myocarditis likely remain asymptomatic and never seek medical attention. The high frequency of exposure to cardiotropic viruses and the observation of a fairly high incidence of ECG abnormalities in apparently healthy individuals support this speculation. 9 The incidence of myocarditis in an autopsy series following traumatic deaths in previously healthy individuals has been reported at 2.2%. 218 Others have reported incidences ranging from 0.11% to as high as 5% in unselected autopsy series. 219, 220 These studies may suggest that at any given time, a significant percentage of the asymptomatic general population has myocarditis.

The most common presentation of myocarditis is an acute febrile syndrome associated with pericardial and sys- temic complaints. Cardiotropic viruses may cause pericardial inflammation, and patients often present with a syndrome of myopericarditis. Chest pain is the most common symptom and is secondary to pericarditis or myocardial injury. 221 A rather dramatic presentation of myocarditis is one indistinguishable from an acute myocardial infarction, complete with chest pain, ECG features suggesting acute ischemic injury, enzymatic evidence of myocardial damage, and echocardiographic or ventriculographic regional wall motion abnormalities, but on endomyocardial biopsy myocarditis is confirmed. [222] [223] [224] Most patients presenting with this acute syndrome completely recover, although there are isolated instances where progressive myocyte loss and cardiac failure or sudden arrhythmic death is reported. 225 The segmental wall motion abnormalities result from virus-mediated injury, although local coronary arteritis and vasospasm have been suggested as possible culprits. 226, 227 Symptoms of right and left ventricular failure and even cardiogenic shock are frequently found in patients with biopsy-proven myocarditis, since it is these symptoms that lead to medical attention. However, the true incidence of heart failure in patients with myocarditis is probably much lower. In patients presenting with recent-onset heart failure and biopsy-proven myocarditis, 50% to 60% have had an antecedent flu-like illness. 225 Neonatal myocarditis is often a fulminant syndrome consisting of fever, tachycardia, tachypnea, cyanosis, and rapid progression to circulatory collapse. 228 Mortality rates are the highest in this subpopulation, approaching 50%. Children are known to present with syncope due to heart block. 229 Other atrial arrhythmias described with myocarditis include sinoatrial block, atrial standstill, AV block, intraatrial conduction abnormalities, atrial tachycardia, flutter, and fibrillation. [230] [231] [232] [233] [234] [235] Histologic evidence of possible myocarditis has been described in up to two thirds of patients with lone atrial fibrillation. 236 Complete heart block has also been described in certain viral infections, such as Epstein-Barr virus or mumps, and also with rickettsiae. [237] [238] [239] Myocarditis may also manifest as myocardial thickening and fibrosis presenting as diastolic dysfunction or restrictive cardiomyopathy, and asymmetric septal thickening resembling hypertrophic cardiomyopathy. [240] [241] [242] Lieberman and coworkers 243 proposed a clinicopathologic description of myocarditis based on the initial manifestations, endomyocardial biopsy, and recovery (fulminant, acute, chronic active, or chronic persistent myocarditis).

Ventricular arrhythmias are frequently encountered in patients with myocarditis, ranging from innocuous premature ventricular contractions to malignant and incessant ventricular tachycardia, and myocarditis is often incriminated in otherwise unexplained ventricular arrhythmias and sudden death. 10, Myocarditis has been documented as a cause of ventricular repolarization abnormalities in athletes with or without arrhythmias. 247, 248 Ventricular arrhythmias may also be precursors to sudden cardiac death in young athletes with occult myocarditis. 249 In autopsy series, myocarditis accounts for 10% to 25% of sudden deaths in young, healthy people. 250, 252, 266, 267 In a population-based retrospective study from Turin, Italy, an incidence of only 0.53% was reported among 17,162 autopsies performed over three decades, 253 but the application of standardized systematic histologic examination and criteria tends to give a higher incidence, in the range of 5%, among autopsies performed at a general hospital. 254 Wesslen and associates 255 reported signs of active, healing, or healed myocarditis in 12 of 16 cases of sudden death in young Swedes. Among high-performance athletes, sudden death due to undiagnosed myocarditis often stirs media attention. 256 Myocarditis has also been anecdotally implicated in sudden infant death syndrome. 257 Ventricular arrhythmias are frequently the initial and most prominent presentation of giant cell myocarditis. [107] [108] [109] [110] 251, 270 Ventricular arrhythmias and sudden death are common in all forms of myocardial failure, but specific immunemediator-induced effects on myocyte electrophysiology could also account for a portion of these arrhythmias. Binah 271 summarized a number of the mechanisms recognized by work in his laboratory and in others. As noted above, perforin elaborated by CTLs is capable of forming membrane channels that pass charged ions, resulting in action potential shortening and diastolic oscillations. 272 In addition, Fas ligand can lengthen the action potential and induce afterpotentials, in part through inhibiting I to and augmenting I CaL . 273 

The physical findings in acute myocarditis are dependent on the extent of myocardial or pericardial involvement, inciting agent (cardiotropic virus), and other factors. Fever occurs occasionally, and in the Myocarditis Treatment Trial (MTT), 274 it was noted in 18% of patients with myocarditis. Sinus tachycardia may frequently accompany the febrile state but is often out of proportion to the fever and is more likely adrenergically mediated, owing to the hemodynamic alterations of the failing heart. Significant ventricular dysfunction may also be associated with hypotension, gallops, murmurs of regurgitation, rales, jugular venous distention, hepatomegaly, ascites, pleural effusions, and peripheral edema. Pericardial involvement may result in a friction rub. The physical findings are not specific for myocarditis.

Patients with myocarditis frequently have serologic evidence of an inflammatory state with elevation of nonspecific markers of inflammation, such as erythrocyte sedimentation rate, C-reactive protein, and leukocyte counts. A fourfold increase in virus-specific IgG titers in the convalescent period is considered reliable evidence of recent infection and is found in 20% of patients with myocarditis. 275, 276 In the MTT, more than half of the patients with biopsy-proven myocarditis had an elevated sedimentation rate. 274 Other markers noted to be elevated in myocarditis include TNF-α, ICAM-1, vascular cell adhesion molecule-1, interleukins, and soluble Fas. 195, 196, 277, 278 Unfortunately, these markers are not specific for myocarditis.

Myocarditis, although associated with myocyte damage and necrosis, results in CK-MB elevation in only 12% of patients with biopsy-proven myocarditis. 279 More recently, Lauer and colleagues 280 reported on CK-MB elevation in only one of fi ve patients with histologic evidence of myocarditis, but cardiac troponin T (cTnT), which is extremely specific for myocardial damage, was elevated in all five. Additionally, cTnT was elevated in 28 patients, of whom 26 had immunohistologic evidence of myocarditis. Thus, cTnT elevation appears to be highly predictive for myocarditis. 280 In an analysis of stored sera on 88 patients from the MTT, 276 cardiac troponin I (cTnI) was elevated in 34% of patients (18 of 53) with myocarditis, compared with 11% (4 of 35) without myocarditis. In contrast, CK-MB values were elevated in only 5.7% of patients (3 of 53) with myocarditis. Further, the cTnI elevations correlated with less than 1 month's duration of heart failure symptoms. 276 Antibodies to cardiac antigens can be detected in the serum of patients with myocarditis. 126,281,282 Anti-α-myosin IgG antibodies may have promise as a diagnostic tool, and, along with other antibodies, probably play a functional role. 283, 284 The clinical efficacy of IgG immunoadsorption 285, 286 in DCM supports this notion (see also Fig. 59.6 ).

Historically, acute myocarditis was diagnosed with the constellation of clinical symptoms, physical signs, and ECG abnormalities. Although no particular feature on the electrocardiogram is pathognomonic of acute myocarditis, sinus tachycardia, repolarization abnormalities, conduction abnormalities, and arrhythmias are common findings. In a series of 45 patients with biopsy-proven myocarditis, Morgera and associates 287 noted an abnormal QRS duration in 45%; abnormal Q waves in 18%; left bundle branch block (LBBB) and right bundle branch block (RBBB) patterns in 18% and 13%, respectively; ST elevation in 16%; T-wave inversions in 16%; and advanced AV block in 16%. In patients presenting earlier in the course of the disease, with symptoms of less than 1 month's duration, 31% had advanced AV block and 47% had ST elevation with T-wave inversions. The latter finding has been noted to portend a poorer prognosis. Other predictors of poor outcome include LBBB, RBBB, and other conduction abnormalities, which seem to suggest active, severe, and extensive myocarditis. 288 Patients may present with sustained ventricular tachycardia, and continuous ECG monitoring of patients with myocarditis often reveals complex ventricular ectopy and nonsustained ventricular tachycardia. 245, 289 Echocardiography is useful in assessing the extent of left ventricular systolic dysfunction, which may range from mild segmental hypokinesis to severe global hypokinesis or akinesis associated with severe congestive heart failure (CHF). 290 Patients presenting with chest pain or arrhythmias without CHF often have normal echocardiograms. The ventricular dimensions may remain normal or may be only mildly enlarged. There may be an increase in left ventricular sphericity and right ventricular elongation and an increase in wall thickness and left ventricular mass with the interstitial edema and compensatory hypertrophy. 241, 291 Restrictive filling patterns in the left ventricle identifying diastolic dys-function have been reported consistently in biopsy-proven myocarditis. 241 Mural thrombi in diffusely hypokinetic ventricles have been reported frequently. 292 Hyperrefractile myocardium and other qualitative and quantitative analyses of myocardial texture have been described to assess the degree of active myocardial inflammation. 293 Pericardial effusion is a helpful echocardiographic finding, reported in 10% of patients with myocarditis, though hemodynamic compromise with cardiac tamponade is infrequent. 293 Urhausen and associates 294 recently demonstrated that cardiac tissue velocity imaging by ultrasound is more sensitive than magnetic resonance imaging (MRI) in some cases in detecting myocarditis with subtle ventricular functional impairment. Imaging of leukocyte-mediated inflammation through ultrasound fracture of phagocytosed microbubbles shows promise as a means for detecting many forms of myocardial inflammation, although the method remains to be fully evaluated in humans. 295 Cardiac scintigraphy has been proposed as a convenient, noninvasive test with high sensitivity to diagnose active myocarditis. Gallium-67 imaging, which identifies areas of increased inflammation, has been studied in clinical settings and noted to have sensitivity and specificity of 83% and 86%, respectively, with a negative predictive value of 98% for the diagnosis of myocarditis. 296 Indium-111 antimyosin monoclonal antibodies have been extensively studied to identify areas of myocyte damage in acute myocarditis. 297, 298 This technique has extremely high sensitivity and often detects myocarditis that, on endomyocardial biopsy, is not seen by routine histologic assessment but is detected by immunohistochemistry. 299 Dec and coworkers 300 studied 74 patients with DCM with radiolabeled antimyosin antibody and endomyocardial biopsy. Thirty-nine patients had abnormal antimyosin scans, but only 11 of 39 had evidence of myocarditis (predictive value of 33%). However, functional improvement was more likely in antimyosin scan-positive patients irrespective of the biopsy. The left ventricular ejection fraction (LVEF) improved significantly in both concordant-positive (scan and biopsy both positive) and discordant-positive (scan positive, biopsy negative) patients, but it did not markedly improve in the negative scan and negative biopsy subset. The investigators proposed that discordant-positive scans represented patients with myocarditis in whom there may have been a sampling error on biopsy, hence the reason for missing the diagnosis. 300 Anastasiou-Nana's group 301 in Athens reported that a combination of minimal or no left ventricular dilatation and a positive indium-111 antimyosin monoclonal antibody scan is highly specific for myocarditis. Other nuclear techniques, such as technetium-99m ( 99m Tc)-MIBI single photon emission computed tomography (SPECT) imaging, 302 may also be useful in detecting myocarditis.

Contrast media-enhanced cardiovascular MRI in patients with myocarditis has also been demonstrated to be an excellent tool in visualizing the location, activity, and extent of inflammation. 303 Early in myocarditis (day 2), the enhancement on MRI signals is accentuated and focal, whereas later (day 84), this seems to be attenuated and more diffuse. 304 Furthermore, the severity of change correlates with prognosis. 305 Myocardial phosphorus-31 magnetic resonance spectroscopy has been utilized in assessing abnormalities in cardiac high-energy phosphate metabolism in patients with DCM and allograft rejection, but its role in the diagnosis of active myocarditis remains to be elucidated. 306 

The antemortem diagnosis of myocarditis was made feasible by the development of the endomyocardial biopsy technique. Myocardial samples could be obtained via a transvascular approach with minimal discomfort to the patient and a low complication rate. Whereas other approaches for acquiring myocardial tissue included percutaneous biopsy and mediastinotomy, 307,308 these were fraught with complications, precluding their acceptance into clinical practice. The safe and successful transvascular endomyocardial biopsy first described by Sakakibara and Konno 309 was readily accepted for surveillance of cardiac allograft rejection in transplant recipients. The use of endomyocardial biopsy for the diagnosis and management of myocarditis was first reported in 1980. 310 Subsequently, many reports 170, 225, 243, [258] [259] [260] [261] [262] [263] [264] 269, [311] [312] [313] [314] [315] [316] [317] [318] [319] [320] [321] [322] [323] [324] [325] [326] [327] [328] [329] documented myocarditis in patients presenting with unexplained heart failure or ventricular arrhythmias (Table 59 .4). However, there was considerable incongruity in the diagnostic criteria used in these largely anecdotal reports. The Dallas criteria were developed in preparation for a large, randomized, multicenter clinical trial of immunosuppressive therapy in myocarditis. 330 These criteria define active myocarditis (see also Fig. 59 .7A) as "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of ischemic damage associated with coronary artery disease." Furthermore, other causes of inflammation (e.g., connective tissue disorders, infection, drugs) should be excluded. 5, 330 The Dallas criteria also defined borderline myocarditis as an inflammatory infiltrate that is sparse and lacks myocyte injury, and often (67%) on repeat biopsy, borderline myocarditis will histologically progress to active myocarditis. 331 A limitation of endomyocardial biopsy is possible sampling error. The inflammation in myocarditis may be patchy or focal, unlike allograft rejection, which is a relatively diffuse process. Although obtaining four samples from the right ventricular septum provides a high sensitivity for detection of allograft rejection in transplant recipients, 332 this may not hold true for myocarditis. In an autopsy study of the right ventricular biopsy technique (10 samples taken from the apical septum), only six of 11 patients dying of myocarditis were correctly identified. Left ventricular biopsy missed the diagnosis in eight of 11. 333 In another study using the standard four to six samples, the sensitivity of right ventricular endomyocardial biopsy was reported at 50%. 334 Dec and colleagues 331 reported that employing repeat left and right ventricular biopsies in patients with suspected myocarditis with an initial negative biopsy increases the yield by 15%. Because an ideal study to evaluate sampling error has not been done, the true yield is unknown, but clearly a negative biopsy does not exclude active myocarditis. In the MTT, only 9% of patients screened had histologic evidence of myocarditis. The European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID) 7 demonstrated a 20% incidence of biopsy-proven myocarditis by expanding the Dallas criteria with the use of newer techniques of PCR and in situ hybridization. As discussed earlier, [6] [7] [8] [9] [10] [11] there is a need for validation of new histologic and nonhistologic criteria for diagnosis of this disease to improve upon the Dallas histologic criteria.

Coronary arteriography is usually normal, although in animal models, coronary vasculitis has been reported. The one major exception is Kawasaki disease, in which coronary artery aneurysms are frequently seen in association with myocarditis. 335 Ventriculograms may demonstrate global or regional ventricular dysfunction, associated valvular regurgitation, and mural thrombi. 336 Localized ventricular aneurysms with normal global systolic function have also been reported. 337 The hemodynamic profiles of patients with acute myocarditis are representative of the extent of myocardial and pericardial involvement. In patients with significant ventricular dysfunction, elevated filling pressures with depressed cardiac output and stroke work indices are seen. A restrictive hemodynamic profile can be seen and must be differentiated from that seen with postviral constrictive pericarditis.

The true natural history of myocarditis is largely unknown because the great majority of cases is perhaps subclinical and resolves without any significant residual cardiac dysfunction. Clinically apparent myocardial dysfunction as seen with acute coxsackievirus B infections also resolves without any adverse sequelae in most cases. It has been estimated that only 12% of patients with clinically suspected acute myocarditis will proceed to develop DCM, 338 but the true incidence is unknown. The murine myocarditis models frequently develop a pathologic process indistinguishable from that of the human form of idiopathic DCM.

The direct link among viral infection, myocarditis, and DCM has not been conclusively proven. Isolation of infectious virus from the heart has been achieved in only a few cases of acute fulminant myocarditis in neonates and infants. 21, 339 Given the hypothesis that DCM may develop after viral infection has been eradicated, the presence of virus in the myocardium is neither sufficient nor necessary to link virally mediated myocarditis with DCM. The indirect evidence of viral etiology of DCM relies on (1) progression of viral myocarditis to DCM in experimental animal models, (2) apparent progression of myocarditis in some patients to DCM, (3) increased enteroviral antibody titers in patients with DCM, (4) presence of viral genomic material in the myocardial tissue of patients with DCM, and (5) improvement of ventricular function in subjects with DCM receiving immunomodulatory treatments. The major limitations are as follows: the relevance of disease in mice to humans is suspect, most cases of DCM are not preceded by documented myocarditis, and epidemiologic serologic evidence is incomplete. Whereas coxsackievirus B IgM antibodies are detected with greater frequency in patients with DCM than in normal controls, the frequency is similar to matched community controls and household contacts. 287, 340 Enteroviral genomic sequences are detected in the myocardium of 8% to 70% of patients with active myocarditis and in 0% to 45% of patients with DCM, but in data derived from most published studies, the average detection frequencies are 25% for active myocarditis, 15% for DCM, and not significantly different from 15% among healthy controls. 288, 341 In a metaanalysis of the association of enteroviruses with human heart disease, Baboonian and Treasure 342 concluded that although the causative role of enteroviruses in acute myocarditis, particularly in children, was supported by an overall odds ratio of 4.4 [confidence interval (CI), 2.4 to 8.2], and the association of DCM was suggested by an overall odds ratio of 3.8 (CI, 2.1 to 4.6), six of 17 studies did not demonstrate an increased presence of viral remnants. The same investigators demonstrated more recently that PCR positivity is not found in minimally affected first-degree relatives of patients with familial DCM, 343 suggesting that in this group, genetic predisposition to viral myocarditis does not underlie the inherited predisposition to development of DCM. In recent studies, other investigators have found strong evidence for a viral link, 344 while others have found no viral vestiges in the myocardium of patients with end-stage heart failure. 345, 346 Regional variation in the etiology of DCM may be responsible in part for the reported differences in PCR positivity.

Responsiveness of patients with DCM to immunomodulatory interventions provides an interesting line of evidence supporting a viral/immune etiology of DCM. One would expect immune suppression to be an effective treatment in DCM if postviral and other forms of autoimmunity play a causative role in the disease. Efficacy of such interventions has been reported in carefully selected patients. 285, 286, [347] [348] [349] Although the link between myocarditis and DCM is unclear, certain prognostic factors are identifiable. The presence of an abnormal QRS complex on ECG correlates with more severe left ventricular damage and is an independent predictor of survival. Left atrial enlargement, atrial fibrillation, and LBBB are also associated with increased mortality. 287 Higher baseline LVEF is positively associated with survival, whereas intensity of conventional therapy at baseline is negatively associated with survival. 274 The presence of right ventricular dysfunction, as evidenced by abnormal right ventricular systolic shortening on echocardiography, was shown to be the most important predictor of death or need for cardiac transplantation in a group of 23 patients with biopsy-proven myocarditis who were followed longterm. 291 In addition, a net increase in LVEF (between initial and final ejection fraction) was associated with improved survival, whereas baseline ejection fraction was not predictive of outcome. The presence and degree of left ventricular regional wall motion abnormalities did not affect the clinical course. 291 Light microscopic findings on biopsy have not been found to predict outcome in myocarditis. However, the extent of myocardial inflammation was a predictor of outcome after surgical ventricular remodeling for heart failure. 350 Higher baseline serum antibodies to cardiac IgG by indirect immunofluorescence was associated with a better LVEF and a smaller left ventricular end-diastolic dimension. 274

General supportive measures for patients with myocarditis include a low-sodium diet, discontinuation of ethanol, and fluid restriction, especially in the presence of heart failure. Patients with myopericarditis may need analgesics for pain control. Recommendations for the limitation of physical activity are based on the murine model of CVB3 myocarditis, in which forced exercise during the acute phase of illness was associated with higher titers of infectious virus, increased inflammatory and necrotic lesions, and mortality. 339, 351, 352 Ibuprofen, indomethacin, and salicylates administered to mice after inoculation with CVB3 also resulted in increased viral titers, increased histologic severity of myocarditis, and increased mortality. 209 This led to the suggestion that even nonsteroidal antiinflammatory drugs should be avoided in patients with active acute myocarditis. The American College of Cardiology Task Force on myopericardial diseases recommends a convalescent period of approximately 6 months after the onset of clinical manifestations before a return to competitive sports. 353 

The management of patients with presumed or confirmed myocarditis is primarily directed toward treatment of CHF, arrhythmias, and symptoms from pericardial disease. Diuretics, vasodilators, and digoxin should be administered to patients with mild-to-moderate systolic dysfunction. Inotropic therapy and mechanical support with intraaortic balloon pump or ventricular-assist devices may be required for patients in refractory cardiogenic shock. Cardiac transplantation is reserved for those patients who do not improve despite the measures described previously.

Although there are multiple studies on the use of angiotensin-converting enzyme inhibitors (ACEIs) in heart failure, 354 the utility of ACEIs in myocarditis has been studied only in the murine model. Early treatment with captopril in a CVB3 myocarditis model resulted in less inflammatory infiltrate, myocardial necrosis, and calcification. Heart weight, heart/body weight ratio, and liver congestion diminished. Even with delayed therapy, a reduction in left ventricular mass and liver congestion was evident. 355 The ACEIs exert a potent vasodilator response, improve pump function, prevent ventricular remodeling, and may have antiarrhythmic properties. Hence, all patients with systolic dysfunction, including those with myocarditis, should be placed on maximally tolerated doses of ACEIs.

The use of beta-blockers in patients with mild-tomoderate heart failure due to DCM has been reported to be beneficial, 356 but once again, no trials in humans with myocarditis have been performed. Metoprolol-treated mice in an acute CVB3 murine myocarditis model have increased viral replication, myocyte necrosis, and 30-day mortality rates. 355 Carteolol, a nonselective beta-blocker, has been studied in a chronic myocarditis model and found to have beneficial effects with improved histologic scores, reduced heart weight and volume, and liver congestion. 357 It appears that in the acute setting, beta-blockers should be avoided, and in the chronic heart failure stage, the nonselective beta-blockers may be beneficial.

Antiarrhythmic therapy may be needed for control of ventricular and supraventricular dysrhythmias. Although the data from clinical trials of antiarrhythmic therapy in heart failure have not shown a primary mortality benefit, patients with active myocarditis were excluded in these trials. Since immunosuppression is probably not helpful in myocarditis 274 and no other specific therapy is available, one might consider treating the arrhythmias in the usual fashion, but there appears to be a rationale for making the diagnosis of myocarditis in patients who do not have profound ventricular dysfunction along with their arrhythmia. First, the majority of patients with myocarditis have a spontaneous resolution. Second, current antiarrhythmic therapy of ventricular tachyarrhythmias is exacting, involving electrophysiologic studies and use of potentially toxic drugs or implantable defibrillators. The benefit of making the diagno-sis of myocarditis is that the patient may require only shortterm protection while the underlying process resolves, which can be provided by using amiodarone or other antiarrhythmic drugs under inpatient monitoring. If myocarditis resolves, antiarrhythmic therapy can be withdrawn. Patients whose arrhythmias fail to improve despite histologic resolution of myocarditis, or who survived cardiac arrest, may be candidates for aggressive electrophysiologic approaches and implantable defibrillators. 244 Temporary and permanent pacemakers may be required in patients presenting with conduction system abnormalities.

Clinical trials of immunosuppressive therapy were first reported in children with clinical evidence of myocarditis, prior to the introduction of endomyocardial biopsy. In two series, in a total of eight children presenting with acute onset of severe CHF, rapid improvement and survival were noted with adrenocorticotropic hormone or hydrocortisone treatment. 358 , 359 Mason and associates 310 reported 10 patients with biopsy-proven myocarditis, half of whom improved with azathioprine and prednisone. Gagliardi and coworkers 360 followed 20 children with biopsy-proven myocarditis who were treated with cyclosporine and prednisone. At 1 year, 10 of 20 patients still had histologic evidence of myocarditis. No patient died or required transplantation. However, there was no control group. The data supporting an immunologic basis of myocarditis resulted in multiple treatment trials using immunosuppressants (Table 59 .5). The average proportion of patients showing improvement with a variety of immunosuppressants was 54%. 361 A large number of the trials predated the development of the Dallas criteria; thus, the histologic definition of myocarditis was not uniform. Immunosuppressive regimens were arbitrary, and the lack of control groups made interpretation of these trials arduous. It was unclear whether immunosuppression was beneficial in those patients with myocarditis, as they can improve spontaneously. Further, the infectious complications of immunosuppression were frequently seen and occasionally reported. 310, 362 The conflicting results from these nonrandomized observations led to the MTT. 274 In a multicenter, prospective, randomized design, the MTT enrolled patients with heart failure of recent onset (<2 years), left ventricular dysfunction (LVEF <45%), and biopsy-proven myocarditis (per the Dallas criteria). The study screened 2333 patients; 214 (9%) had endomyocardial biopsy evidence of myocarditis, and 111 patients had a qualifying LVEF of less than 45% and agreed to enrollment. Patients were randomized to three treatment arms: prednisone and cyclosporine, prednisone and azathioprine, and no immunosuppressant treatment. All patients received conventional therapy for heart failure. The prednisone and azathioprine group was subsequently eliminated owing to low patient recruitment in the trial. Patients were treated for 24 weeks, and the primary end point was comparison of the mean increase in LVEF at 28 weeks. Secondary analysis of other markers of left ventricular function, survival, and several immune parameters was performed. At both 28 and 52 weeks, no difference in LVEF was observed in immunosuppressive-treated patients compared with untreated patients. At 1 and 5 years, there was no difference in survival or need for cardiac transplantation between groups (Fig. 59.5) . On multivariate analysis, better baseline LVEF, less intensive conventional therapy, and shorter illness duration were independent predictors of improvement in LVEF during follow-up. Analysis of immunologic variables (cardiac IgG, circulating IgG, natural killer and macrophage activity, helper T-cell level) suggested an association between better outcome and a more robust immune response. A higher level of cardiac IgG was associated with a higher LVEF and a smaller left ventricular size. The mortality rate for the entire trial was 20% at 1 year and 56% at 4.3 years. The results of the MTT were important for diagnostic management because the authors recommended that in patients with unexplained CHF, the performance of endomyocardial biopsy for the sole purpose of instituting immunosuppressive therapy was not warranted.

Nonetheless, certain subgroups may benefit from immunosuppressant therapy, including those with GCM, hypersensitivity myocarditis, or cardiac sarcoidosis. Using a multicenter database, Cooper and colleagues 108 reviewed 63 patients with GCM. The rate of death or cardiac transplanta-tion was 89%. Median survival was 5.5 months from symptom onset to death or transplantation. The median survival in patients treated with corticosteroids was 3.8 months versus 3.0 months in untreated patients. However, patients treated with corticosteroids and azathioprine had an average survival of 11.5 months. Cyclosporine in combination with corticosteroids, corticosteroids and azathioprine, and corticosteroids, azathioprine, and orthoclone OKT3 survived an average of 12.6 months. The uncontrolled nature of this report decreases the reliability of its conclusions.

Patients with myocarditis associated with a known immune-mediated disease, such as systemic lupus erythematosus, may benefit from immunosuppressive therapy. Other potential indications for a trial of immunosuppressant therapy include failure of myocarditis to resolve, progressive left ventricular dysfunction despite conventional therapy, continued active myocarditis on biopsy, or fulminant myocarditis that does not improve within 24 to 72 hours of full hemodynamic support, including mechanical assistance, and persistent ventricular tachycardia or fibrillation.

Smaller studies have used differing immunosuppressant regimens. Kühl and Schultheiss 363 treated 31 patients with biopsies classified as immunohistologically positive (more then two cells per high-power field and expression of adhesion molecules), negative Dallas criteria, and left ventricular dysfunction. Patients were treated with conventional therapy for 3 months, followed by gradual tapering of methylprednisolone doses over 24 weeks (following biopsy and LVEF response). Therapy was associated with an improvement in ejection fraction in 64% and improved New York Heart Association (NYHA) functional class in 77%. Four patients (12%) had no change in ejection fraction despite improvement in inflammatory infiltrates. However, study conclusions are limited by the absence of a control group.

Drucker and coworkers 364 retrospectively reviewed 46 children with congestive cardiomyopathy and Dallas criteria of borderline or definite myocarditis. Twenty-one patients were treated with intravenous IgG (2 g/kg over 24 hours) and were compared to 25 historical controls. Overall survival was not improved, although there was a trend toward improvement in 1-year survival rates in the treated group. In the intravenous IgG group, the left ventricular function was improved and persisted after adjustment for age, biopsy status, and use of ACEIs and inotropes.

In a comparative study of IFN-α, thymomodulin, and conventional therapy in patients with biopsy-proven myocarditis or idiopathic DCM, an improvement in the active treatment groups was reported for ejection fraction (at rest and during exercise), maximal exercise time, functional class, and ECG abnormalities. 365 In 10 patients with CHF, NYHA class III or IV, with symptoms of less than 6 months' duration, intravenous IgG resulted in an improvement in LVEF and a functional improvement to NYHA class I or II at 1 year of follow-up, in all nine patients who survived, regardless of biopsy results. 366 Perhaps strategies with alternative immunosuppressive regimens and different diagnostic criteria will be more successful in demonstrating the utility of immunosuppressants. The ESETCID 7,367 is a prospective multicenter, placebocontrolled, double-blind study intended to address the natural course of myocarditis, myopericarditis, pericarditis, and The treatment regimens include conventional therapy with diuretics, ACEIs, digoxin, and antiarrhythmics or defibrillators; specific therapy for CMV and enteroviral myocarditis; and prednisolone and azathioprine for myocarditis without detectable virus. The duration of blinded therapy is 6 months, with follow-up for 24 months. The possible utility of more flexible diagnostic criteria for identification of responders to immunosuppressive therapy was recently suggested in a retrospective analysis by Frustaci and colleagues. 10 They found that the patients who had improved with immunosuppression had detectible circulating cardiac-specific autoantibodies but no detectible viral genomic material in their myocardium, while nonresponders had the opposite findings. These observations could be explained by successful suppression of an autoimmune response without the liability of suppressing ongoing antiviral immune activity.

Immunomodulatory therapies should be considered in cases of myocarditis that display ongoing adverse immune and autoimmune activity. Immunosuppressive drug therapy, intravenous IgG, TNF-α, and immunoadsorption are the forms of immunomodulation discussed above that have been used in humans (Fig. 59.6 ). Immunoadsorption has been applied primarily in dilated cardiomyopathy, but may hold promise in myocarditis, 349 perhaps especially in phase 2 ( Fig.  59 .2A) of lymphocytic myocarditis. Manipulation of cytokines, chemokines, and other factors that regulate proinflammatory and antiinflammatory processes 191, 196, 201, [368] [369] [370] [371] should receive attention in the development and assessment of new immunomodulatory therapies.

Myocarditis has emerged as a special indication for device therapy in recent years. Circulatory-assist devices are especially attractive in myocarditis because the disease is usually self-limited. As a result, a relatively short period of circulatory assistance may allow time for the myocardium to recover and the injurious infectious, immune, and autoimmune processes to dissipate. This concept has been successfully tested in patients with severe heart failure due to myocarditis. [372] [373] [374] Implanted cardioverter-defibrillator devices have been used to treat ventricular tachyarrhythmias commonly associated with myocarditis. 265 While such therapy may be lifesaving, consideration should always be given to antiarrhythmic drug therapy with protracted monitoring so as to avoid device implantation if possible. 244 Those patients with myocarditis who have survived cardiac arrest are candidates for implantable defibrillator devices.

In a small series (n = 12) composed predominantly of female patients (75%), the outcome of patients with active lymphocytic myocarditis confirmed by histologic examination of the explained heart was significantly worse than in controls undergoing transplantation for other diagnoses. 375 This concern has not been validated in the analysis of outcome of 14,055 cardiac transplant recipients in the registry of the International Society for Heart and Lung Transplantation.

One-year actuarial survival in all groups transplanted (idiopathic DCM, myocarditis, peripartum cardiomyopathy, versus other diagnoses) was 80%. 376 Nonetheless, myocarditis may recur in the transplanted heart. 377 Prevention Prevention of myocarditis is an important developing strategy given the likelihood that a substantial proportion of cases of DCM worldwide are the result of preceding or ongoing myocarditis. Several strategies have been considered, including immunization against the most common cardiotropic viruses, 112, 202, [378] [379] [380] [381] functional disablement of the Coxsackie-adenovirus sarcolemmal receptor, 382, 383 and early induction of immune tolerance. 384 While immunization seems to have the greatest potential, scientific, medical, geographic, and political impediments are formidable.

The advances in treatment strategies for HIV-infected patients have successfully resulted in prolonged survival times, and noninfectious complications of AIDS, such as dementia and heart disease, have become increasingly prevalent. Early in the history of the AIDS epidemic, reports emerged of a rapidly fatal DCM affecting HIV-infected patients. 385, 386 Since the early reports, several clinical and echocardiographic series 56, [387] [388] [389] [390] [391] have suggested that a subgroup of HIV-infected patients are predisposed to the development of progressive heart disease. In a prospective echocardiographic survey of 296 HIV-infected adults over a period of 4 years, 44 patients were found to have significant cardiac dysfunction. Dilated cardiomyopathy occurred in 13 of 44 and was strongly associated with a CD4 count of less than 100/mm 3 and poorer survival. 391 It has been estimated that clinically significant cardiac disease occurs in 6% to 7% of HIV-seropositive individuals. 392 An interesting hypothesis to explain the high frequency of dilated heart muscle disease is the presence of myocarditis in HIV-infected patients with left ventricular dysfunction. Reilly and colleagues 393 reported in an autopsy series of 58 consecutive AIDS patients a significantly higher incidence of myocarditis in those with clinically apparent cardiac disease or DCM. There have been other reports of higher prevalence of myocarditis in an endomyocardial biopsy series of HIV-seropositive patients compared with those without risk factors for HIV who were biopsied for suspected myocarditis. 394 Human immunodeficiency virus-related myocarditis has unique and atypical immunopathogenic features. It is characterized by increased CD8 T lymphocytes and sole induction of MHC class I, perhaps as a part of the systemic depletion of CD4 T cells. The myocarditis may not be readily apparent on histology owing to the accompanying lymphopenia, and special immunohistology and histochemistry techniques may need to be employed. 395 Although in situ hybridization techniques have demonstrated HIV-1 transcripts in cardiac myocytes, interstitial dendritic cells, and endothelial cells, the pathologic significance of this finding is still unclear because patients with evident transcripts may or may not have clinical disease. Also, it is not evident that myocyte injury is a result of direct cytotoxicity of the virus, transcripts, cytokines, or other cardiotropic viruses. 396 A large number of HIV-seropositive patients with left ventricular dysfunction also manifest evidence of nonpermissive or latent infection of myocytes with CMV immediate-early (CMV IE-2) genes. Although evidence for classic intranuclear inclusions of active lytic CMV infection is rarely found, there is increasing speculation that the latent viral infection may be responsible for enhanced MHC expression and provide a stimulus for ongoing immune injury, as seen with most models of myocarditis. 397 A role for direct cytokine-mediated cardiac injury has also been proposed in HIV-infected populations with myocardial dysfunction. Both TNF-α and IL-6, known to be elevated in HIV infection, directly inhibit cardiac contractility in vitro, 368 and the former has been implicated in causing myocardial dysfunction. Increased catecholamines may be responsible for microvascular spasm and chronic ischemic dysfunction.

The clinical management of patients with HIV-related myocarditis and cardiomyopathy is targeted toward improving congestive symptoms, afterload reduction, and digitalis for improved neurohormonal axis. A specific role for antiviral therapies is controversial, since medications like zidovudine and IFN-α are themselves recognized as cardiotoxins. Zidovudine has been known to result in premature termination of myocyte mitochondrial DNA chain replication. 398 

Despite worldwide eradication of smallpox, the bioterrorism threat arising from the existence of stored variola virus has prompted military and civilian smallpox vaccination programs in the United States. 399 Myocarditis emerged as a known, rare complication of smallpox vaccination during the eradication effort in the 1950s and 1960s. Its incidence varied with the vaccinia strain used to produce the vaccine, and with the method used to detect myocarditis. The true incidence is not known. Current vaccination programs use the original New York City Board of Health strain of vaccinia (Dryvax) and new vaccines. While the occurrence of myocarditis in the United States's current military Dryvax vaccination program appears to be higher (0.01%, or about one in 10,000) 400 than historical estimates, its incidence after new vaccines has not been determined. Previously vaccinated individuals have a much lower risk of developing myocarditis. Full functional and symptomatic recovery occurs in most patients. While involvement of eosinophils has been noted, 401 the mechanisms responsible for postvaccination myocarditis are not known.

Bacterial infection of the myocardium occurs frequently in association with infective endocarditis, usually in the form of myocardial abscesses adjacent to the valve ring (see Chapter 4) . Myocardial involvement has also been reported in association with a wide range of bacterial pathogens in the absence of endocarditis. 42, [402] [403] [404] [405] [406] [407] [408] With most of these agents, myocardial involvement is uncommon and occurs principally in the setting of overwhelming systemic infection.

Cardiac involvement after streptococcal infection is usually manifested as acute rheumatic fever, which develops 2 to 3 weeks after onset of pharyngitis and has a distinctive histologic appearance (see Chapter 4) . Streptococcal pharyngitis may also be associated with a nonrheumatic form of myocarditis that occurs concurrently with the febrile illness. [409] [410] [411] [412] The most common clinical manifestations are chest pain and marked ST-segment and T-wave abnormalities on the electrocardiogram, which correlate with segmental wall motion abnormalities observed with echocardiography. 409 Cardiomegaly and CHF are uncommon. Histologic examination reveals lymphocytic infiltrates and myocyte necrosis in the absence of Aschoff bodies, similar to the findings in viral or idiopathic myocarditis. 412 Bacteria are not present in the myocardium, and it is hypothesized that inflammation is caused by streptococcal exotoxins in a manner similar to that in diphtheritic myocarditis.

Although vaccination has virtually eliminated diphtheria in most Western nations, it remains an important public health problem in many underdeveloped countries, 413 and may be the most common etiology of myocarditis worldwide. Infection with C. diphtheriae is usually confined to the respiratory mucosa. Systemic manifestations are due to secretion of a potent exotoxin. The ECG abnormalities suggesting myocardial involvement are present in a high proportion of patients, 414 but clinical evidence of cardiac dysfunction occurs in only 10% to 25% of cases. Nevertheless, cardiac involvement is the most common cause of death in fatal infections. 415 Disturbances of AV conduction, including bundle branch blocks and complete AV block, are observed frequently in affected patients and are associated with a mortality rate of 60% to 90%. Patients may also present with progressive cardiac dilatation and CHF. Histologic study reveals diffuse mononuclear cell infiltrates associated with myocyte necrosis. 416 Corticosteroid therapy does not appear to be effective in the prevention or treatment of diphtheritic myocarditis, although only one prospective trial has been performed. 417 One report suggested that administration of carnitine may decrease the incidence and severity of cardiac involvement. 418 Spirochetal Myocardial Disease LYME DISEASE Lyme disease is caused by the spirochetal organism B. burgdorferi, which is transmitted to humans by certain species of deer ticks in endemic areas of North America, Europe, and Asia. The acute phase of the illness is characterized by fever, myalgia, lymphadenopathy, and a characteristic rash known as erythema chronicum migrans. 419 The organism persists in many tissues, and chronic manifestations include arthritis and a variety of neurologic syndromes. Manifestations of cardiac involvement develop in 4% to 10% of patients at an average of 4.8 weeks (range, 4 days to 7 months) after the acute illness. 41, 420, 421 Disturbances of AV conduction are the most common manifestations, occurring in 87% of cases, with complete or high-grade block in more than 50%. The AV block is usually supra-Hisian, with a narrow complex escape rhythm. 422 Temporary transvenous pacing is required frequently, but AV block almost always resolves within 7 to 10 days. Endomyocardial biopsy may reveal lymphocytic infiltrates with associated myocyte necrosis, 422 and spirochetes may be identified in biopsy specimens. Lyme carditis occasionally develops in patients without a preceding rash or other symptoms of acute Lyme disease. 423 Therapy with a 2 to 3 week course of antibiotics (doxycycline, amoxicillin or cefuroxime) is recommended for patients with Lyme carditis. 420, 421 Antibiotic therapy has proved effective in the prevention and treatment of chronic arthritic and neurologic syndromes, but its use in cardiac disease has not been tested prospectively. Evidence of diffuse myocardial involvement is common, including evolving STsegment and T-wave abnormalities on the electrocardiogram, reversible abnormalities of left ventricular wall motion, 420 and diffuse myocardial uptake on gallium scan. 422 One fatal case of pancarditis has been reported, but frank heart failure is uncommon.

A high incidence of positive serologies for B. burgdorferi was reported in European patients with chronic DCM, and in two patients the organism was cultured from myocardial biopsies. 424, 425 It has been suggested that unrecognized Lyme carditis may be responsible for a small but significant proportion of cases of idiopathic DCM.

Evidence of severe myocarditis is present at autopsy in a high proportion of fatal cases of leptospirosis and relapsing fever. 425, 426 Nonspecific ECG abnormalities are common in these diseases, but clinical evidence of left ventricular dysfunction is rare.

Although previously uncommon, the incidence of fungal infections of the heart has increased markedly since the early 1970s. This increased incidence is due to several factors, including the increasing use of antibiotics, immunosuppressive agents for transplantation, and chemotherapy, as well as the increasing application of cardiac surgery and the increasing prevalence of intravenous drug abuse. 427 Candida INFECTION The most common fungal organisms causing cardiac infection are Candida species. Candida endocarditis occurs most frequently after thoracic surgery and in intravenous drug abusers. Immunocompromised patients, on the other hand, are more likely to develop Candida myocarditis without involvement of the valves or endocardium, usually in the setting of disseminated systemic infection. [428] [429] [430] Autopsy studies reveal extensive myocardial involvement in 10% to 63% of patients who die of systemic candidiasis.

Histologically, Candida myocarditis consists of focal abscesses (usually microscopic, although gross nodules may be present) interspersed with areas of normal myocardium. Clinical manifestations typically include nonspecific ECG abnormalities, disturbances of AV conduction, including complete heart block, and tachyarrhythmias. 428 Cardiomegaly and CHF are rare. Myocardial involvement is usually not recognized antemortem.

Myocardial involvement is present in 22% of patients with disseminated aspergillosis, 431 and myocardial invasion is almost always present in patients with Aspergillus endocarditis. As in other tissues, histology is characterized by microscopic and macroscopic abscess formation. 431, 432 Extensive vascular invasion by fungal hyphae results in thrombosis and coagulation necrosis. Although Aspergillus endocarditis has been treated successfully, myocarditis is uniformly fatal.

Cardiac involvement in actinomycosis occurs in only 2% of cases and usually develops by direct extension from a contiguous focus of pulmonary or mediastinal infection. [433] [434] [435] Hematogenous seeding of the myocardium occurs occasionally. Myocardial involvement is characterized by necrotizing abscess formation with masses of mycelial bodies and characteristic sulfur granules. In many cases, cardiac symptoms are absent, but patients may present with chest pain characteristic of pericarditis, 433 pericardial tamponade, 434 or CHF. 435 

Myocardial involvement has rarely been reported in immunocompromised patients with disseminated coccidioidomycosis and cryptococcosis. [431] [432] [433] [434] [435] [436] [437] [438] [439] Cardiac involvement is usually not clinically apparent antemortem, although death due to progressive CHF has been reported. 439 Cardiac involvement with blastomycosis and histoplasmosis is extremely uncommon and usually results from direct extension from a contiguous intrathoracic focus.

Rocky Mountain spotted fever caused by infection with Rickettsia rickettsii is characterized by a diffuse vasculitis, and in fatal cases, death is usually due to vascular collapse. Vasculitis of the coronary vessels may also be present, and lymphocytic infiltrates with myocyte necrosis are present in approximately 50% of fatal cases. 440, 441 Although cardiac dilatation and cardiogenic pulmonary edema occur infrequently, 442 echocardiography demonstrates systolic left ventricular dysfunction in the majority of patients. 443, 444 Clinical evidence of myocarditis has been reported in association with scrub typhus due to Rickettsia tsutsugamushi, whereas Q fever (Coxiella burnetii) usually causes endocarditis in its chronic form.

It is estimated that 10 to 18 million people in South and Central America are infected with T. cruzi, and Chagas' cardiomyopathy resulting from this infection is the most common cause of CHF and cardiac death in these endemic areas. 445, 446 The parasite is transferred to humans by triatomine insects known as reduviid bugs. The clinical course of infection is characterized by an acute phase, an indeterminate or latent phase of variable duration, and a chronic phase. 446, 447 After inoculation, parasites are disseminated throughout the body, with the highest concentrations appearing in striated and cardiac muscle and autonomic ganglia. A lesion may appear at the point of entry, and an acute illness develops, characterized by fever, myalgia, edema of the face and lower extremities, hepatomegaly, and generalized lymphadenopathy. Because of the nonspecific nature of the symptoms, the acute phase of the disease is usually unrecognized.

Rarely, acute inflammatory myocarditis develops during the acute phase, with ECG abnormalities, cardiomegaly, and CHF. Histologic examination in these cases demonstrates inflammatory infiltrates adjacent to myocytes containing large numbers of intracellular parasites. These findings suggest that cardiac manifestations during the acute phase of the illness may be due to direct lysis of myocytes by parasites. 448, 449 The acute illness resolves over a period of weeks to months, and patients enter the indeterminate phase. These patients are asymptomatic, with low-level parasitemia, and antibodies to T. cruzi are present. Although the electrocardiogram is normal, echocardiography and left ventricular cineangiography demonstrate focal wall motion abnormalities in a high proportion of cases, most commonly involving the left ventricular apex and posterior wall. Endomyocardial biopsy is frequently normal but may reveal hypertrophy, fibrosis, and inflammatory infiltrates in up to 37% of patients without clinical manifestations. 450 Manifestations of chronic Chagas' disease develop in 30% to 70% of infected patients after a highly variable period, which may be as long as 50 years. 445, 449 Involvement of autonomic ganglia may cause megacolon or megaesophagus, but the heart is the organ most commonly affected. Histology is characterized by focal areas of inflammation or fibrosis interspersed with areas of normal myocardium. Endomyo-cardial biopsy reveals myocarditis in approximately 60% of patients. 451, 452 This process frequently involves the specialized conducting tissue, and therefore disturbances of AV conduction, especially RBBB with or without associated left anterior fascicular block, are present in up to 60% of patients. Complete heart block may require permanent transvenous pacing. Ventricular arrhythmias are also frequent, and the initial manifestation of the disease may be sudden death due to ventricular tachyarrhythmia or complete heart block. Decreased ventricular function is present in almost all patients with chronic Chagas' disease, and in its most advanced form, Chagas' disease presents as a congestive cardiomyopathy with four-chamber dilatation. A characteristic apical aneurysm is usually present. [453] [454] [455] Left ventricular thrombus is frequently observed, and systemic embolization is common. 456, 457 This advanced form of the disease is usually fatal within a few years.

Diagnosis of chronic Chagas' cardiomyopathy is dependent on detection of circulating antibodies to T. cruzi by one of several serologic methods. Parasites are usually not detected in the myocardium, but low-level parasitemia can be demonstrated by hemoculture or xenodiagnosis, using uninfected reduviid bugs allowed to ingest the patient's blood. 446 The pathogenic mechanisms leading to myocardial injury, in some patients occurring many years after the initial infection, are poorly understood. The presence of inflammatory infiltrates in the absence of detectable parasites suggests the possibility of autoimmune injury, as postulated for viral and idiopathic myocarditis. Support for this hypothesis includes the demonstration of antibodies to T. cruzi as well as antiidiotypic antibodies that cross-react with myocyte antigens. 458, 459 Histologic studies demonstrate loss of autonomic ganglia, and physiologic studies are suggestive of marked autonomic dysfunction. [460] [461] [462] Withdrawal of parasympathetic tone may lead to excess sympathetic stimulation, which can cause cardiomyopathy. Histologic studies also demonstrate abnormalities of the microvascular bed, 447, 463 and in vitro experiments demonstrate altered endothelial cell function and increased platelet-endothelial cell adhesion. 447, 464 All three reports suggest that progressive focal myocardial disease is the result of ischemia due to obstruction of the microvascular bed.

Treatment of chronic Chagas' cardiomyopathy is supportive, with the use of standard therapy for CHF. Dynamic cardiomyoplasty has resulted in symptomatic improvement in some patients. The role for left ventricular reduction or the commonly known Batista procedure is controversial. Antiarrhythmic therapy may be indicated for sustained ventricular tachyarrhythmias, and a permanent pacemaker should be implanted in patients with high-degree AV block.

Two antiparasitic drugs are available for the treatment of American trypanosomiasis. Both nifurtimox and benznidazole decrease the level and duration of parasitemia and decrease mortality in patients with acute Chagas' disease. 446 Low-level parasitemia persists in most treated patients, however, and it is unclear whether therapy in the acute phase decreases the incidence of subsequent progression to chronic Chagas' disease. Whereas earlier studies with these drugs have not been shown to decrease progression from latent phase to chronic disease or to decrease symptoms or improve cardiac function in patients with chronic disease, 446, 447 the recent studies with itraconazole and allopurinol have shown partial success with parasitologic cure and normalization of ECG changes in nearly half the patients. 465 In a randomized, placebo-controlled trial of benznidazole, there was successful negative seroconversion of 55% of patients with early chronic disease as manifested by seropositivity for T. cruzispecific antibodies after treatment for 60 days. 466 Immunosuppressive therapy in patients with malignancies or after organ transplantation has been associated with reactivation causing acute Chagas' disease. 467, 468 Reactivation of Chagas' disease in this setting has usually responded promptly to therapy. [469] [470] [471] AFRICAN TRYPANOSOMIASIS African trypanosomiasis is caused by Trypanosoma gambiense or T. rhodanese and characteristically presents with progressive somnolence owing to central nervous system involvement. Autopsy studies demonstrate a pancarditis involving the mural and valvular endocardium as well as the myocardium in up to 50% of fatal cases. [472] [473] [474] [475] The conduction system and autonomic ganglia may also be involved. Nonspecific abnormalities are often present on the electrocardiogram, but other clinical manifestations of the frequent cardiac involvement are apparently uncommon.

Patients with acute infection by T. gondii are usually asymptomatic, but they may have a transient syndrome of fever and lymphadenopathy. The infection usually persists in a latent phase, with cysts deposited predominantly in the brain and myocardium. Immunosuppression after chemotherapy, in transplant recipients, and in patients with AIDS may be associated with disseminated infection characterized by severe encephalitis and myocarditis. [476] [477] [478] [479] Myocarditis after transplantation occurs frequently in seronegative recipients of hearts from seropositive donors. [477] [478] [479] Endomyocardial biopsy demonstrates intracellular Toxoplasma pseudocysts and a mixed interstitial infiltrate, frequently including eosinophils ( Fig. 59.7D ). Toxoplasma myocarditis can be successfully prevented by a 6-week course of pyrimethamine imitated after early transplantation or treated with pyrimethamine and sulfadiazine.

Cardiac involvement in metazoal infections is uncommon. Up to 2% of patients with echinococcosis have cardiac cysts. [480] [481] [482] These patients may present with pericardial or atypical chest pain, CHF owing to inflow or outflow obstruction, ventricular arrhythmias, or pulmonary hypertension owing to diffuse pulmonary embolization of scolices. The diagnosis is usually documented by two-dimensional echocardiography, and surgical excision is indicated, when possible, even in asymptomatic patients.

Trichinosis, caused by the parasite T. spiralis, is usually a benign syndrome characterized by fever, myositis, and eosinophilia. Mild, asymptomatic myocardial involvement is probably common, as suggested by frequent ECG abnormalities and pericardial effusion noted by echocardiography. 483 Rarely, a severe myocarditis develops, which is the apparent cause of death in most fatal cases. [484] [485] [486] Eosinophils are prominent in the interstitial infiltrate. T. spiralis does not become encysted in the heart, and larvae are seldom identified in the myocardium. Myocardial injury is thought to be immune mediated, and therapy with corticosteroids is generally recommended, although prospective trials have not been performed owing to the infrequent occurrence of this syndrome.

The mucocutaneous lymph node syndrome or Kawasaki disease occurs predominantly in children under the age of 10 years and is most prevalent in Japan. 487, 488 It has been recognized worldwide, and in the United States and the developed world, it has replaced rheumatic fever as the most common cause of acquired heart disease in children. It is widely believed to have an infectious etiology, but no agent has yet been identified. Its diagnosis is based on recognition of clinical features of the illness, which include remittent high-spiking fever with distinctive conjunctival injection, anterior uveitis, strawberry tongue with erythema, dryness, fissuring and peeling of the lips and mouth, erythematous truncal rash, redness of palms and soles with periungual desquamation, and cervical lymphadenopathy. 489 The principal cardiovascular manifestation of the disease is a multisystem arteritis with frequent involvement of the coronary arteries. 490 Coronary arteritis leads to aneurysm formation and thrombosis. The most common cause of death is myocardial infarction due to aneurysm rupture or coronary occlusion. Myocardium obtained by endomyocardial biopsy or at autopsy reveals histologic evidence of myocarditis in a high proportion of patients. [490] [491] [492] [493] Segmental wall motion abnormalities and nonspecific ECG changes are frequently present in the absence of coronary aneurysms. 494, 495 These findings have been attributed to myocarditis, but they might also reflect ischemia due to small vessel arteritis. Congestive heart failure in the absence of infarction is uncommon. Intravenous gamma-globulin and high-dose aspirin are effective in the prevention of coronary aneurysms and thrombosis, 496 but their effect on myocarditis is not known.

Giant cell myocarditis is a rare but frequently fatal disorder. It is defined histologically by extensive but patchy myocyte necrosis with areas of intense multicellular inflammatory infiltration that includes histiocytes, lymphocytes, and the characteristic multinucleated giant cells (Fig. 59.7B) . 105, [497] [498] [499] There has been a great deal of controversy as to whether GCM and cardiac sarcoidosis are distinct pathologic entities because multinucleated giant cells in GCM seldom organize to form granulomas. 107,500,501 Litovsky and associates 501 showed that GCM is characterized by myocytic destruction mediated by cytotoxic T cells, macrophagic giant cells, and eosinophils. In contrast, cardiac sarcoid is an interstitial granulomatous disease without myocytic necrosis. 270 Although the etiology of GCM is unknown, it has been associated with a medley of autoimmune disorders and perhaps is immunologically mediated. Thymomas, systemic lupus, rheumatoid arthritis, Wegener's granulomatosis, ulcerative colitis, chronic hepatitis, myasthenia gravis, myositis, pernicious anemia, Takayasu's arteritis, and lymphomas have been associated with GCM. [502] [503] [504] [505] [506] [507] [508] [509] The clinical presentation of GCM may mimic lymphocytic myocarditis, although arrhythmias and heart failure are usually more severe and rapidly progressive. 510, 511 Frequently, patients with GCM present with conduction system abnormalities, ventricular tachycardia, or even sudden cardiac death. [107] [108] [109] [110] 251, 270, 502, 512, 513 Giant cell myocarditis has also been reported to present as asymmetric septal hypertrophy. 512 The natural history of GCM is obscure owing to its rare occurrence, but the isolated reports in the literature suggest that it carries a poor prognosis. Davidoff and coworkers 110 reported that 70% of patients with GCM required cardiac transplantation or died during a 4-year follow-up period compared with the 29% of patients with lymphocytic myocarditis. Cooper and colleagues 108 reported on 63 patients with GCM collected in a worldwide registry. The registry patients had an 89% rate of death or need for transplantation, which was significantly worse than that for the 111 patients with lymphocytic myocarditis seen in the MTT. The median survival with GCM was 5.5 months. The patients treated with immunosuppressive regimens including cyclosporine, azathioprine, and prednisone had an average cardiac survival of 12.3 months compared with 3.0 months for the untreated patients. The rate of recurrent GCM in the transplanted patients was 25% (nine of 36).

The role of immunosuppressive therapy for GCM is unknown, but at least anecdotal and registry reports suggest possible benefit of cyclosporine and prednisone with or without azathioprine. Cardiac transplantation remains the last therapeutic resort for these patients, although there is risk of recurrent disease, 108,514,515 which seems to be associated with abatement of immunosuppressive therapy after transplantation 516 and may represent atypical rejection in the allograft. 517 It usually resolves with intensification of the immunosuppressive regimen.

Eosinophilic Myocarditis Loffler 518 first described the association of eosinophils with cardiac disease, and reported "endocarditis parietalis fibroplastica" in association with eosinophilia. The endocardial disease with eosinophilia is well recognized and extensively reviewed elsewhere. 519, 520 Myocardial involvement is rare and frequently fatal; hence, diagnosis is often made postmortem. Endomyocardial biopsy is essential to the antemortem diagnosis of eosinophilic myocarditis (Fig. 59.7C ). 521 Myocarditis is believed to represent a more fulminant and necrotic form of the endocardial disease. 522 Eosinophils have the ability to secrete highly toxic cationic proteins into areas of inflammation and to produce harmful oxygen radicals and potent lipid mediators, leading to myocyte necrosis as seen in proximity to degranulating cosinophils. 523 Animal experiments have confirmed that exposure of myocytes to eosinophil granule proteins is lethal, and ventricular function in the intact heart is reduced in hypereosinophilic states. 524 Eosinophilic myocardial infiltrates have been reported in association with profound eosinophilia caused by an allergic diathesis, parasitic infection, drug hypersensitivity, vasculitis, or Churg-Strauss syndrome, 66, 525, 526 but eosinophilic myocarditis can occur in the absence of profound eosinophilia. 527 Further, eosinophilic myocarditis may present as acute myocardial infarction, sudden death, cardiogenic shock, or nonspecific chest pain and dyspnea.

The natural history of eosinophilic myocarditis is usually swift and ominous with rapid evolution to refractory heart failure or intractable arrhythmias, leading to death. Early biopsy-aided histologic confirmation is fundamental to antemortem diagnosis. Clinical improvement may occur with corticosteroid therapy. 527 Cardiac Sarcoidosis Sarcoidosis is a multiorgan, noncaseating granulomatous disorder of unknown etiology. Histologically, it may involve the lung, lymph nodes, skin, liver, spleen, parotid glands, and heart. 528 Right heart failure owing to pulmonary manifestations of pulmonary hypertension and pulmonary fibrosis is the predominant cardiac finding. 529 Asymptomatic cardiac involvement is common, with a quarter of the patients having sarcoid granulomas in the heart at autopsy. 530 Characteristically, the noncaseating granulomas infiltrate the ventricular walls and become fibrotic. They may involve the conduction system, although there is no definite predilection for specialized tissues. There may be transmural involvement with fibrous replacement of portions of the myocardium and aneurysm formation. 531 The fibrous transition of granulomas may result in early diastolic dysfunction, but as the disease progresses and with extensive involvement, systolic impairment occurs. Whereas cardiac involvement in sarcoidosis commonly occurs as part of the systemic affliction, isolated cardiac sarcoidosis in the absence of systemic disease has been described. 532 The clinical presentation of cardiac sarcoidosis is variable and may depend on the amount of myocardium replaced with granulomas and the amount and location of scar tissue. Rhythm abnormalities and conduction disorders predominate, 533 although asymptomatic patients with mildly restrictive filling patterns may elude medical attention. Patients with CHF may show clinical features of restrictive cardiomyopathy or DCM. 534 Papillary dysfunction with mitral regurgitation and pericardial involvement with effusiveconstrictive disease have also been described. 533 Radionuclide myocardial imaging with thallium 201 and gallium 67 is helpful in identifying patients with myocardial involvement. 535 Magnetic resonance imaging has also been proposed as a diagnostic modality. 536, 537 Histologic diagnosis with endomyocardial biopsy is corroborative, but a negative biopsy does not rule out the possibility, owing to sampling error.

The combination of bilateral hilar adenopathy and myocardial disease suggests cardiac sarcoidosis in a young person. Corticosteroids are indicated when myocardial involvement, conduction abnormalities, and ventricular arrhythmias are present. 538 Patients with scintigraphic uptake of gallium 67 may be more responsive to corticosteroid therapy. 539 Perma-nent pacemakers may be needed to treat the conduction abnormalities. Implantable defibrillators may be utilized in the prevention of sudden death. 540 Heart failure is treated in the conventional manner, whereas heart transplantation is reserved for intractable heart failure. 541 Heart-lung transplants are performed infrequently for patients with pulmonary involvement, but there is a significant risk of recurrent disease. 541 Peripartum Myocarditis/Cardiomyopathy Virchow and Porak first reported the association of pregnancy with DCM in 1870 in an autopsy series. 542 Peripartum myocarditis/cardiomyopathy occurs in one of every 3,000 to 15,000 pregnancies. The incidence is higher in Africa, and it increases with older age, multiparity, multiple gestations, and prior history of peripartum myocarditis/cardiomyopathy. Peripartum cardiomyopathy is currently believed to be a myocarditis of unknown etiology, perhaps an infectious, autoimmune, or idiopathic process. The viral myocarditis hypothesis stems from the observations that pregnant mice are more susceptible to cardiotropic viruses, with increased viral replication, 543 and with the increased hemodynamic burden of pregnancy, the myocardial lesions worsen. 544 Recently, it has been postulated that after delivery, the rapid degeneration of the uterus results in fragmentation of tropocollagen by enzymatic degradation. This releases actin, myosin, and their metabolites, and antibodies are formed that then cross-react with the myocardium. 542 An association between tocolytic therapy and cardiomyopathy has also been reported. 545 While the diagnosis of peripartum myocarditis/cardiomyopathy is traditionally made during the last trimester or during the first 5 months postpartum, earlier occurrence has been reported. 546 The presentation is usually of decompensated ventricular systolic failure in the absence of any identifiable cardiac pathology. The LVEF normalizes in approximately 50% of women and is more likely to normalize if the initial LVEF is >30%. Therapy is tailored to the decompensated state with diuretics, digoxin, and vasodilators (ACEIs are contraindicated in pregnancy). Inotropic therapy may be needed for supporting those in cardiogenic shock, along with the use of mechanical circulatory-assist devices. Although there are anecdotal reports of benefit of immunosuppressive therapy, 547 the routine use of these agents cannot be recommended; in fact, the only indication would be biopsy-proven fulminant myocarditis. Cardiac transplantation is an alternative therapeutic option and may be offered to those with intractable heart failure, but it is preferred that transplantation be delayed. The early outcome after transplantation in these patients is often unfavorable, with increased allograft rejection, and the natural history of peripartum myocarditis/cardiomyopathy suggests that more than half of the patients have spontaneous resolution. 548 There are perhaps two different subgroups. One presents with a rapidly progressive, fulminant course with often nearcomplete resolution of myocardial dysfunction within days and excellent long-term prognosis. 547 The other group has late, insidious onset and presents with progressively worsening heart failure with poor prognosis. It is often difficult to differentiate this from the common variety of DCM.

Myocarditis is a focal or diffuse inflammation of the myocardium, which has multiple infectious and noninfectious etiologies. Autoimmunity, triggered most often by viral infections, is a prominent pathophysiologic mechanism of myocarditis. Overt and clinically inapparent myocarditis is an important cause of dilated cardiomyopathy. Virus-induced lymphocytic myocarditis progresses through three stages: active viral infection, autoimmunity, and dilated cardiomyopathy. Myocarditis is no longer a diagnosis of exclusion; histology, histochemistry, DNA and RNA detection, tissue and circulating antibody detection, and a variety of imaging techniques can be used together or, in some cases, independently to make the diagnosis and to establish the disease stage. Treatment of myocarditis must be tailored to the phase of disease. Many new therapies based on knowledge of the molecular pathophysiology of myocarditis are under development. 

Traite' de la structure du Coeur, de Son Action et de Ses Maladies

Praktisch Diagnostik der Inneren Kronkheiten mit Vorzuegli der Ruecksicht und pathologische Anatomie

Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies

Myocarditis, a histopathologic definition and classification

Clinical merit of endomyocardial biopsy

The European Study of Epidemiology and Treatment of Cardiac Inflammatory Disease (ESETCID)

Immunohistological diagnosis of myocarditis. Potential role of sarcolemmal induction of the MHC and ICAM-1 in the detection of autoimmune mediated myocyte injury

Should endomyocardial biopsy be performed for detection of myocarditis? A decision analytic approach

Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders

Viral heart disease: molecular diagnosis, clinical prognosis, and treatment strategies

Etiology of mild acute infectious myocarditis. Relation to clinical features

Myocarditis in connection with viral infections in Finnish conscripts

Influenza A1 myocarditis in conscripts

Electrocardiographic studies in patients with abnormalities in serial examinations with standard leads during acute infectious diseases. I. Occurrence of abnormalities in the ST-T complex of chest leads in resting electrocardiograms suggestive of localized myocardial lesions

Virological investigations in congestive cardiomyopathy

Virological study of idiopathic cardiomyopathy: serological study of virus antibodies and immunofluorescent study of myocardial biopsies

Epidemiology of viral infections of the heart

Acute myocarditis. Serologic diagnosis, clinical findings and follow-up

Reverse radioimmunoassays of IgM and IgG antibodies to Coxsackie B viruses in patients with acute myopericarditis

Acute myocarditis. Rapid diagnosis by PCR in children

Detection of viruses in myocardial tissues by polymerase chain reaction. Evidence of adenovirus as a common cause of myocarditis in children and adults

Fatal parvovirus B19-associated myocarditis clinically mimicking ischemic heart disease: an endothelial cell-mediated disease

Prevalence of the parvovirus B19 genome in endomyocardial biopsy specimens

Frequency and quantity of the parvovirus B19 genome in endomyocardial biopsies from patients with suspected myocarditis or idiopathic left ventricular dysfunction

High prevalence of viral genomes and multiple viral infections in the myocardium of adults with "idiopathic" left ventricular dysfunction

High prevalence of cardiac parvovirus B19 infection in patients with isolated left ventricular diastolic dysfunction

Cytomegalovirus myocarditis

Cytomegalovirus myocarditis

Cytomegalovirus associated inflammatory heart muscle disease

Cytomegalovirus myocarditis in transplanted heart verified by endomyocardial biopsy

Virus infections in heart transplant recipients and evidence for involvement of the heart

Dilated cardiomyopathy associated with hepatitis C virus infection

Chronic variant of myocarditis associated with hepatitis C virus infection

Hepatitis C virus infection and heart diseases: a multicenter study in Japan

Hepatitis C virus from the hearts of patients with myocarditis and cardiomyopathy

Diphtheria in the eighties: experience in a south Indian district hospital

Fatal myocarditis secondary to Salmonella septicemia in a young adult

Cardiac involvement due to Salmonella typhi infections in children

Immunologic aspects of vasculitis and cardiovascular disease

Lyme carditis: an important cause of reversible heart block

Symptomless myocarditis and myalgia in viral and Mycoplasma pneumoniae infections

A loud third heart sound and asymptomatic myocarditis during Mycoplasma pneumoniae infection

Chlamydial infections of the heart

A clinical and epidemiological study of "ornithosis" caused by Chlamydia psittaci and Chlamydia pneumoniae (strain TWAR)

Myocarditis caused by Chlamydia pneumoniae (TWAR) and sudden unexpected death in a Swedish elite orienteer

A progressive pericardial effusion caused by psittacosis

Myocardial disease in Rocky Mountain spotted fever: clinical, functional, and pathologic findings

Serodiagnosis of Q-fever by enzyme-linked immunosorbent assay (ELISA)

Cardiac involvement is a constant finding in acute Chagas' disease: a clinical, parasitological and histopathological study

Toxoplasmosis in heart and heart and lung transplant recipients

Successful treatment of Toxoplasma gondii myocarditis in an AIDS patient

Prevalence of toxoplasma myocarditis in patients with the acquired immunodeficiency syndrome

Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome

Echocardiography detects myocardial damage in AIDS: prospective study in 102 patients

Cardiomyopathy associated with antiretroviral therapy in patients with HIV infection: a report of six cases

Trichinosis with ventilatory failure and persistent myocarditis

Cardiac hypersensitivity to 5-aminosalicylic acid

Hypersensitivity myocarditis caused by an allergic reaction to cefaclor

Fatal methyldopa-associated granulomatous hepatitis and myocarditis

Giant cell myocarditis as a manifestation of drug hypersensitivity

Myocarditis associated with clozapine treatment

Drug related myocarditis. I. Hypersensitivity myocarditis

Erythema multiforme and hypersensitivity myocarditis caused by ampicillin

Acute necrotizing eosinophilic myocarditis as a manifestation of severe hypersensitivity myocarditis. Antemortem diagnosis and successful treatment

Hypersensitivity myocarditis in heart transplant candidates

Myocarditis related to clozapine treatment

Myocarditis and cardiomyopathy associated with clozapine

Reversible myocarditis in a patient receiving clozapine

Hypersensitivity myocarditis

Hypersensitivity myocarditis with ephedra use

Pet foodderived penicillin residue as a potential cause of hypersensitivity myocarditis and sudden death

Hypersensitivity myocarditis and hepatitis associated with imipramine and its metabolite, desipramine

Myocarditis associated with methyldopa therapy

Adverse reactions to drugs used in the treatment of tuberculosis

Donehower RC. Clinical toxicities encountered with paclitaxel (Taxol)

Myocarditis related to drug hypersensitivityo

Hypersensitivity myocarditis associated with ephedra use

Drug-induced toxic myocarditis

Montelukast and Churg-Strauss syndrome

Acute myocarditis associated with tetanus vaccination

Spontaneous pneumomediastinum and myocarditis following Ecstasy use: a case report

Kerosene poisoningvaried systemic manifestations

Adverse cardiac effects associated with clozapine

Severe myocarditis following high-dose interleukin-2 administration

Interstitial myocarditis following the clinical and experimental use of sulfonamide drugs

Fatal azide-induced cardiomyopathy presenting as acute myocardial infarction

Cardiomyopathy associated with high-dose interleukin-2 therapy

Toxic myocarditis in paracetamol poisoning

Acute myocardiotoxicity during 5-fluorouracil therapy

Lethal cardiac toxicity after cisplatin and 5-fluorouracil chemotherapy

Cardiovascular manifestations of systemic lupus erythematosus

Cardiovascular involvement in systemic lupus erythematosus

Cardiac involvement in rheumatoid arthritis. An echocardiographic study

Primary heart disease in systemic sclerosis (scleroderma): advances in clinical and pathologic features, pathogenesis, and new therapeutic approaches

Polymyositis, dermatomyositis and inclusionbody myositis

Cardiac involvement in polymyositis

The carditis and aortitis of ankylosing spondylitis

HLA-B27-associated cardiac disease

The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations

The cardiovascular manifestations of the hypereosinophilic syndrome. Prospective study of 26 patients, with review of the literature

Heart disease and the eosinophil

Eosinophilia and endomyocardial fibrosis

Myocarditis with multinucleated giant cells detected in biopsy specimens

Giant cell myocarditis

Distinct forms of myocarditis

Idiopathic giant-cell myocarditis-natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators

Life-threatening ventricular arrhythmias associated with giant cell myocarditis (possibly sarcoidosis)

Giant cell versus lymphocytic myocarditis. A comparison of their clinical features and long-term outcomes

Giant-cell myocarditis

Advances in the understanding of myocarditis

Myocarditis and dilated cardiomyopathy. An inflammatory link

Viral latency: a link between myocarditis and dilated cardiomyopathy?

Transgenic expression of replication-restricted enteroviral genomes in heart muscle induces defective excitation-contraction coupling and dilated cardiomyopathy

From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death

What lessons can be learned from animal model studies in viral heart disease?

Coxsackievirus B3 murine myocarditis: a pathologic spectrum of myocarditis in genetically defined inbred strains

Cardiac persistence of cardioviral RNA detected by polymerase chain reaction in a murine model of dilated cardiomyopathy

Persistence of viral genome into late stages of murine myocarditis detected by polymerase chain reaction

In situ detection of enteroviral genomes in myocardial cells by nucleic acid hybridization: an approach to the diagnosis of viral heart disease

Coxsackievirus infection as a trigger of cardiac autoimmunity

Induction of multiple heart autoantibodies in mice with coxsackievirus B3-and cardiac myosin-induced autoimmune myocarditis

T cell mimicry in inflammatory heart disease

Identification of a putative shared epitope between Coxsackie virus B4 and alpha cardiac myosin heavy chain

induces novel antigens recognized by cytolytic T lymphocytes

Coxsackievirus B3 infection alters plasma membrane of neonatal skin fibroblasts

Expression of costimulatory molecules B7-1, B7-2, and CD40 in the heart of patients with acute myocarditis and dilated cardiomyopathy

Antibodies against ADP-ATP carrier enhance Ca2+ current in isolated cardiac myocytes

Expression of class I and class II major histocompatibility antigens in normal and transplanted human heart

Induction of major histocompatibility complex antigens within the myocardium of patients with active myocarditis: a nonhistologic marker of myocarditis

Major histocompatibility complex class I and class II expression by myocytes in cardiac biopsies posttransplantation

Vascular HLA-DR expression correlates with pathologic changes suggestive of ischemia in idiopathic dilated cardiomyopathy

Predictive value of immunofluorescence and electron microscopic evaluation of endomyocardial biopsies in the diagnosis and prognosis of myocarditis and idiopathic dilated cardiomyopathy

Influence of cytokines and immunosuppressive drugs on major histocompatibility complex class I/II expression by human cardiac myocytes in vitro

Abnormal expression of histocompatibility and mitochondrial antigens by cardiac tissue from patients with myocarditis and dilated cardiomyopathy

HLA class II (DR and DQ) antigen associations in idiopathic dilated cardiomyopathy. Validation study and meta-analysis of published HLA association studies

Anti-idiotypic antibodies to a polyomavirus monoclonal antibody recognize cell surface components of mouse kidney cells and prevent polyomavirus infection

Autoanti-idiotype: a basis for autoimmunity and a strategy for antireceptor antibodies

Naturally occurring anti-idiotypic antibodies-mechanisms for autoimmunity and immunoregulation?

Anti-idiotype-pulsed B cells in the induction and expression of autoimmune myocarditis

Viral myocarditis leading to cardiomyopathy: do cytokines contribute to pathogenesis?

Cytokines and autoimmune disease

Neutrophil adherence to isolated adult canine myocytes. Evidence for a CD18-dependent mechanism

Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils

Interleukin-2: inception, impact, and implications

Cytokines: coordinators of immune and inflammatory responses

Induction of fibroblast proliferation by human mononuclear leukocyte-derived proteins

Mechanisms of immune-mediated myocyte injury

Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness

Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophageconditioned medium

The role of the NO pathway in the control of cardiac function

Contractile depression and expression of proinflammatory cytokines and iNOS in viral myocarditis

The role of inducible nitric oxide synthase in the host response to Coxsackievirus myocarditis

Suppression of cytokines and nitric oxide production, and protection against lethal endotoxemia and viral myocarditis by a new NF-kappaB inhibitor

Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia

Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart

Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha

Increased serum levels of circulating intercellular adhesion molecule-1 in patients with myocarditis

Increased circulating cytokines in patients with myocarditis and cardiomyopathy

Augmentation of pathogenesis of coxsackievirus B3 infections in mice by exogenous administration of interleukin-1 and interleukin-2

Detection of transforming growth factor-b1 in Coxsackie B3 virus-induced murine myocarditis

Concepts of autoimmunity applied to idiopathic dilated cardiomyopathy

Progressive interstitial collagen deposition in Coxsackievirus B3-induced murine myocarditis

Myocardial remodeling in viral heart disease: Possible interactions between inflammatory mediators and MMP-TIMP system

Prevention of encephalomyocarditis virus myocarditis in mice by inactivated virus vaccine

Treatment of viral myocarditis with ribavirin in an animal preparation

Ribavirin treatment of murine coxsackievirus B3 myocarditis with analysis of lymphocyte subsets

Prevention of viral myocarditis with recombinant human leukocyte interferon alpha A/D in a murine model

Modification of viral myocarditis in mice by interleukin-6

Effects of intranasal administration of recombinant murine interferon-gamma on murine acute myocarditis caused by encephalomyocarditis virus

Effects of prednisolone on acute viral myocarditis in mice

A nonsteroid anti-inflammatory drug exacerbates Coxsackie B3 murine myocarditis

Coxsackievirus B3 murine myocarditis: deleterious effects of nonsteroidal anti-inflammatory agents

Immunosuppression with high doses of cyclophosphamide reduces the severity of myocarditis but increases the mortality in murine Coxsackievirus B3 myocarditis

Effect of delayed captopril therapy on left ventricular mass and myonecrosis during acute coxsackievirus murine myocarditis

Impact of FK 506 on myocarditis in the enteroviral murine model

Synergistic effects of tacrolimus and human interferon-alpha A/D in murine viral myocarditis

Therapeutic effect of anti-tumor necrosis factor-alpha on the murine model of viral myocarditis induced by encephalomyocarditis virus

Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone. Suppression of natural killer cell activity and tumor necrosis factor-alpha production

The use of cytokine inhibitors. A new therapeutic insight into heart failure

Occurrence and significance of myocarditis in trauma

A classification of 1402 cases

Myocarditis in autopsy

Four faces of acute myopericarditis

Viral myocarditis mimicking acute myocardial infarction

Myocarditis confirmed by biopsy presenting as acute myocardial infarction

Coxsackie viral myocarditis causing transmural right and left ventricular infarction without coronary narrowing

Demographic features and prevalence of idiopathic myocarditis in patients undergoing endomyocardial biopsy

Viral coronary arteritis and myocardial infarction

Coronary artery vasospasm complicating acute myocarditis. A rare association

Textbook of Pediatric Infectious Diseases. Philadelphia: WB Saunders

Stokes-Adams attacks due to acute nonspecific myocarditis in childhood

Biopsy evidence of atrial myocarditis in an athlete developing transient sinoatrial disease

Myocarditis manifesting as persistent atrial standstill

Resolution of atrial standstill in a child with myocarditis

Clinical and electrophysiological characteristics of atrial standstill

Acute myocarditis associated with transient marked myocardial thickening and complete atrioventricular block

Atrial flutter complicating neonatal Coxsackie B2 myocarditis

Histological substrate of atrial biopsies in patients with lone atrial fibrillation

Complete heart block in Epstein-Barr myocarditis

Complete heart block in mumps myocarditis

Acute rickettsial myocarditis and advanced atrioventricular block: diagnosis and treatment aided by endomyocardial biopsy

Sudden increase in left ventricular mass secondary to acute myocarditis

Left ventricular diastolic dysfunction in lymphocytic myocarditis as assessed by Doppler echocardiography

Reversible asymmetric septal hypertrophy in acute myocarditis. Serial findings of two-dimensional echocardiogram and thallium-201 scintigram

A clinicopathologic description of myocarditis

Arrhythmias associated with myocarditis

24-Hour electrocardiographic recordings in mild acute infectious myocarditis

Incessant automatic ventricular tachycardia complicating acute Coxsackie B myocarditis

Brief report: healed myocarditis as a cause of ventricular repolarization abnormalities in athlete's heart

Role of myocarditis in athletes with minor arrhythmias and/or echocardiographic abnormalities

Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles

Sudden cardiac death in Air Force recruits. A 20-year review

Sudden death in idiopathic giant cell myocarditis

Incidence of myocarditis. A 10-year autopsy study from Malmo

Prevalence of myocarditis at autopsy in

An increase in sudden unexpected cardiac deaths among young Swedish orienteers during 1979-1992

Sudden death in young athletes. Lessons from the Hank Gathers affair

Myocarditis misdiagnosed as sudden infant death syndrome (SIDS)

Results of endomyocardial biopsy in patients with spontaneous ventricular tachycardia but without apparent structural heart disease

Cardiac histologic fi ndings in patients with life-threatening ventricular arrhythmias of unknown origin

Unexpected myocardial disease in patients with life threatening arrhythmias

Safety and utility of endomyocardial biopsy in infants, children and adolescents: a review of 66 procedures in 53 patients

Endomyocardial biopsy approach in cases with ventricular arrhythmias

Cardiomyopathy and myocarditis in children with ventricular ectopic rhythm

Prevalence of myocarditis in idiopathic dysrhythmias: role of endomyocardial biopsy and efficacy of steroid therapy

Results of biventricular endomyocardial biopsy in survivors of cardiac arrest with apparently normal hearts

Causes of sudden cardiac death in young Australians

Sudden death in young adults: a 25-year review of autopsies in military recruits

Sudden adult death: a medico-legal series of 77 cases between

A clinicopathologic study on a cause of idiopathic cardiomyopathy and arrhythmia and conduction disturbance employing endomyocardial biopsy

Intractable ventricular tachycardia in a patient with giant cell myocarditis, thymoma and myasthenia gravis

Cytotoxic lymphocytes and cardiac electrophysiology

Effects of purified perforin and granzyme A from cytotoxic T lymphocytes on guinea pig ventricular myocytes

Electrophysiologic perturbations and arrhythmogenic activity caused by activation of the Fas receptor in murine ventricular myocytes: role of the inositol trisphosphate pathway

A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators

A six year study of Coxsackie B virus infections in heart disease

Elevations of cardiac troponin I associated with myocarditis. Experimental and clinical correlates

ICAM-1 and VCAM-1 molecules in the endomyocardial biopsy specimens-patients with clinically suspected myocarditis (abstract)

Levels of soluble Fas in patients with myocarditis, heart failure of unknown origin, and in healthy volunteers

Incidence and clinical characteristics of myocarditis

Cardiac troponin T in patients with clinically suspected myocarditis

Autoantibodies against human ventricular myosin in sera of patients with acute and chronic myocarditis

Circulating cardiac-specific autoantibodies as markers of autoimmunity in clinical and biopsy-proven myocarditis. The Myocarditis Treatment Trial Investigators

Circulating cardiac autoantibodies in dilated cardiomyopathy and myocarditis: pathogenetic and clinical significance

Antimyosin autoantibodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis

Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy

Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: three-month results from a randomized study

Electrocardiography of myocarditis revisited: clinical and prognostic significance of electrocardiographic changes

Long-term followup of electrocardiographic findings in patients with acute myocarditis proven by endomyocardial biopsy

Lymphocytic myocarditis presenting as unexplained ventricular arrhythmias: diagnosis with endomyocardial biopsy and response to immunosuppression

Echocardiography in acute infectious myocarditis: relation to clinical and electrocardiographic findings

Right ventricular dysfunction: an independent predictor of adverse outcome in patients with myocarditis

Recurrent left ventricular mural thrombi in a patient with acute myocarditis

Echocardiographic findings in myocarditis

Images in cardiovascular medicine. Diagnosis of myocarditis by cardiac tissue velocity imaging in an olympic athlete

Noninvasive imaging of inflammation by ultrasound detection of phagocytosed microbubbles

Gallium-67 imaging in patients with dilated cardiomyopathy and biopsy-proven myocarditis

Indium-111 monoclonal angiomyosin antibody imaging in the diagnosis of acute myocarditis

Non-invasive detection of myocyte necrosis in myocarditis and dilated cardiomyopathy with radiolabelled antimyosin

Corrrelation of antimyosinscintigraphy with histological and immunohistological findings in the endomyocardial biopsy in patients with clinically suspected myocarditis

Antimyosin antibody cardiac imaging: its role in the diagnosis of myocarditis

Indium-111 monoclonal antimyosin cardiac scintigraphy in suspected acute myocarditis: evolution and diagnostic impact

99mTc-MIBI myocardial perfusion imaging in myocarditis

Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology

Contrast media-enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis

Long-term follow-up of patients paragraph sign with acute myocarditis by magnetic paragraph sign resonance imaging

Contributions of 31P-magnetic resonance spectroscopy to the understanding of dilated heart muscle disease

Percutaneous myocardial biopsy of the left ventricle. Experience in 198 patients

Exploratory Mediastinotomy in Primary Myocardial Disease

Endomyocardial biopsy

Treatment of acute inflammatory myocarditis assisted by endomyocardial biopsy

Electron microscopic investigation of endomyocardial biopsy samples in hypertrophy and cardiomyopathy. A semiquantitative study in 48 patients

Diagnosis and classification of myocarditis by endomyocardial biopsy

Absence of evidence of myocarditis in endomyocardial biopsy specimens from patients with dilated (congestive) cardiomyopathy. S

Acute myocarditis. Role of histological and virological examination in the diagnosis and assessment of immunosuppressive treatment

The results of transvenous endomyocardial biopsy can frequently be used to diagnose myocardial diseases in patients with idiopathic heart failure. Endomyocardial biopsies in 100 consecutive patients revealed a substantial incidence of myocarditis

Quantitative evaluation of inflammation in biopsy specimens from idiopathically failing or irritable hearts: experience in 80 pediatric and adult patients

Active myocarditis in the spectrum of acute dilated cardiomyopathies: Clinical features

histologic correlates and clinical outcome

Immunosuppressive therapy of biopsy proven myocarditis: experiences with corticosteroids and cyclosporin

Recent experience in the diagnosis of myocarditis

Endomyocardial biopsy in patients with unexplained congestive heart failure

The use of endomyocardial biopsy in heart failure

Lymphocytic myocarditis and dilated cardiomyopathy: treatment with immunosuppressive agents

Diagnostic and prognostic utility of right-sided catheterization and endomyocardial biopsy in idiopathic dilated cardiomyopathy

Diagnostic endomyocardial biopsy findings in 160 consecutive patients: the Yugoslavian experience

Immunohistological evidence for a chronic intramyocardial inflammatory process in dilated cardiomyopathy

Ten-year experience with endomyocardial biopsy in myocarditis presenting with congestive heart failure: frequency, pathologic characteristics, treatment and follow-up

Critical analysis of endomyocardial biopsies from patients suspected of having cardiomyopathy. I: Morphological and morphometric aspects

The utility of the Dallas criteria for the histopathological diagnosis of myocarditis in endomyocardial biopsy specimens (abstract)

Borderline myocarditis: an indication for repeat endomyocardial biopsy

Endomyocardial biopsy detection of acute rejection in cardiac allograft recipients

Evaluation of postmortem endomyocardial biopsy specimens from 38 patients with lymphocytic myocarditis: implications for role of sampling error

Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis

Myocardial infarction in Kawasaki disease: clinical analyses in 195 cases

Ventriculographic findings in the convalescent stage in eleven cases with acute myocarditis

Localized left ventricular aneurysms with normal global function caused by myocarditis

Diagnosing and treating active myocarditis

Viral myocarditis. A review

Similar prevalence of enteroviral genome within the myocardium from patients with idiopathic dilated cardiomyopathy and controls by the polymerase chain reaction

Enteroviral myocarditis and dilated cardiomyopathy: A review of clinical and experimental studies

Meta-analysis of the association of enteroviruses with human heart disease

Absence of viral nucleic acids in early and late dilated cardiomyopathy

Evidence of viral infection in the myocardium of American and Japanese patients with idiopathic dilated cardiomyopathy

No evidence for persistent enterovirus infection in patients with end-stage idiopathic dilated cardiomyopathy

Study on microbial persistence in end-stage idiopathic dilated cardiomyopathy

Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure

Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress

Immunoadsorption in lupus myocarditis

Myocardial inflammatory cell infiltrates in cases of dilated cardiomyopathy as a determinant of outcome following partial left ventriculectomy

Exercise in coxsackie B3 myocarditis: effects on heart lymphocyte subpopulations and the inflammatory reaction

Coxsackievirus myocarditis-with special reference to acute and chronic effects

26th Bethesda conference: recommendations for determining eligibility for competition in athletes with cardiovascular abnormalities. Task Force 3: hypertrophic cardiomyopathy, myocarditis and other myopericardial diseases and mitral valve prolapse

ACE inhibitors in non-ischaemic heart failure: results from the MEGA trials

Beneficial effects of captopril in acute coxsackievirus B3 murine myocarditis

Adrenergic beta-blocking agents in congestive heart failure due to idiopathic dilated cardiomyopathy

Betablocker treatment of dilated cardiomyopathy. Beneficial effect of carteolol in mice

Myocarditis of unknown etiology (Fieldler's?) treated with ACTH; report of a case in a 7-year-old boy with improvement

Acute aseptic myocarditis: corticosteroid therapy

Dilated cardiomyopathy caused by acute myocarditis in pediatric patients: evolution of myocardial damage in a group of potential heart transplant candidates

Immunosuppressive therapy in experimental and clinical myocarditis

Lack of objective improvement in ventricular systolic function in patients with myocarditis treated with azathioprine and prednisone

Treatment of chronic myocarditis with corticosteroids

Gamma-globulin treatment of acute myocarditis in the pediatric population

Long-term follow up of patients with dilated heart muscle disease treated with human leucocytic interferon alpha or thymic hormones initial results

Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy

The European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID). First epidemiological results

Negative inotropic effects of cytokines on the heart mediated by nitric oxide

Immunomodulating agents for the management of heart failure with myocarditis and cardiomyopathy-lessons from animal experiments

Modulation of cytokine production and protection against lethal endotoxemia by the cardiac glycoside ouabain

Role of cytokines in autoimmune myocarditis and cardiomyopathy

Rescue of a child with fulminant myocarditis using percutaneous cardiopulmonary support

Bridge to recovery with a left ventricular assist device for fulminant acute myocarditis

Assessment of myocardial recovery in a patient with acute myocarditis supported with a left ventricular assist device: a case report

Results of heart transplantation for active lymphocytic myocarditis

Heart transplantation in dilated heart muscle disease and myocarditis

Recurrent giant cell myocarditis after transplantation

Vaccination of Balb/c mice against enteroviral mediated myocarditis

High yield production of an inactivated coxsackie B3 adjuvant vaccine with protective effect against experimental myocarditis

Vaccination procedures against Coxsackievirus-induced heart disease

Immunogenicity of a DNA vaccine for coxsackievirus B3 in mice: protective effects of capsid proteins against viral challenge

The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease

Viral myocarditis: receptors that bridge the cardiovascular with the immune system?

Nasal administration of cardiac myosin suppresses autoimmune myocarditis in mice

AIDS in a Haitian woman with cardiac Kaposi's sarcoma and Whipple's disease

Cardiac manifestations of human immunodeficiency virus infection: a two-dimensional echocardiographic study

Comparison among acquired immune deficiency syndrome patients with and without clinical evidence of cardiac disease

Prevalence of cardiac abnormalities in human immunodeficiency virus infection

Human immunodeficiency virus related heart disease during 560 patient-years of follow-up (abstract)

Prevalence and incidence of left ventricular dysfunction in patients with human immunodeficiency virus infection

Heart muscle disease related to HIV infection: prognostic implications

Emerging patterns of heart disease in human immunodeficiency virus infection

Frequency of myocarditis, left ventricular dysfunction and ventricular tachycardia in the acquired immune deficiency syndrome

Dilated heart muscle disease associated with HIV infection

HIVassociated myocarditis. Pathology and immunopathology

Immunopathogenesis of HIV-1-associated cardiomyopathy

In situ detection of human cytomegalovirus immediate-early gene transcripts within cardiac myocytes of patients with HIV-associated cardiomyopathy

Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells

Smallpox vaccination and myopericarditis: a clinical review

Incidence and follow-up of inflammatory cardiac complications after smallpox vaccination

Eosinophiliclymphocytic myocarditis after smallpox vaccination

Congestive heart failure in the course of typhoid fever

Myopericarditis as an initial presentation of meningococcemia. Unusual manifestation of infection with serotype W135

Myocarditis in legionnaires' disease

Myocarditis with microabscess formation caused by Listeria monocytogenes associated with myocardial infarct

Typhoid fever with myocarditis

Serologic evidence for Chlamydia trachomatis myocarditis

Carditis associated with Mycoplasma pneumoniae infection

Streptococcal tonsillitis and acute nonrheumatic myopericarditis

Atrioventricular block complicating acute streptococcal tonsillitis

Acute nonrheumatic perimyocarditis complicating streptococcal tonsillitis

Myocarditis associated with acute nasopharyngitis and acute tonsillitis

Principles and Practice of Infectious Diseases

Diphtheric myocarditis

Cardiac complications of diphtheria

Diphtheritic myocarditis. A histochemical and electron microscopic study

Failure of corticosteroid therapy to prevent diphtheritic myocarditis or neuritis

The protective effect of carnitine in human diphtheric myocarditis

Clinical pathologic correlations of Lyme disease

Early Lyme disease

Cardiac involvement in Lyme disease: manifestations and management

Lyme carditis. Electrophysiologic and histopathologic study

Complete heart block as the sole presentation of Lyme disease

Isolation of Borrelia burgdorferi from the myocardium of a patient with longstanding cardiomyopathy

Lyme borreliosis as a cause of myocarditis and heart muscle disease

In: Mandell GL, ed. Principles and Practice of Infectious Diseases

Cardiac fungal infections: review of autopsy findings in 60 patients

Candida myocarditis without valvulitis

Cardiac candidiasis in cancer patients

The potentially lethal problem of cardiac candidosis

Aspergillus pancarditis following bone marrow transplantation for chronic myelogenous leukemia

Aspergillus myocarditis

Primary actinomycosis of the pericardium

Pericardial actinomycosis with cardiac tamponade from a contiguous thoracic lesion

Cardiac actinomycosis

Unusual manifestations in a cardiac transplantation patient

Overwhelming myocarditis due to Cryptococcus neoformans in an AIDS patient

Cryptococcal myocarditis in acquired immune deficiency syndrome

Chagas' heart disease in the United States

Myocardial involvement in Rocky Mountain spotted fever

Cardiac manifestations of Rocky Mountain spotted fever

Cardiopulmonary dynamics in a severe case of Rocky Mountain spotted fever

Myocardial function in Rocky Mountain spotted fever: echocardiographic assessment

M-mode echocardiographic abnormalities in Rocky Mountain spotted fever

The indeterminate form of human chronic Chagas' disease: a clinical epidemiological review

Trypanosoma species (American trypanosomiasis Chagas" disease): biology of trypansomes

Pathophysiological insights into the cardiomyopathy of Chagas' disease

Eosinophil activation in acute and chronic chagasic myocardial lesions and deposition of toxic eosinophil granule proteins on heart myofibers

Ultrastructural characteristics of different stages of human chagasic myocarditis

Right ventricular endomyocardial biopsy in chronic Chagas' disease

Electrophysiologic findings in long-term asymptomatic chagasic individuals

Cardiac morbidity and mortality due to Chagas' disease: prospective electrocardiographic study of a Brazilian community

M-mode and two-dimensional echocardiography in chronic Chagas' heart disease. A clinical and pathologic study

Echocardiographic features of impaired left ventricular diastolic function in Chagas's heart disease

Left ventricular cineangiography in Chagas' disease: detection of early myocardial damage

The usefulness of the resting electrocardiogram for characterizing acute Chagas' heart disease in the rat

Chagas' heart disease and myocardial infarct. Incidence and report of four necropsy cases

Association of elevated anti-sarcolemma, anti-idiotype antibody levels with the clinical and pathologic expression of chronic Chagas myocarditis

Major Trypanosoma cruzi antigenic determinant in Chagas' heart disease shares homology with the systemic lupus erythematosus ribosomal P protein epitope

Increased capacity of the coronary arteries in chronic Chagas' heart disease: further support for the neurogenic pathogenesis concept

Functional evaluation of sympathetic and parasympathetic system in Chagas' disease using dynamic exercise

Plasma norepinephrine in Chagas' cardioneuromyopathy: a marker of progressive dysautonomia

Microvascular changes as a cause of chronic cardiomyopathy in Chagas' disease

Enhanced platelet adherence and aggregation in Chagas' disease: a potential pathogenic mechanism for cardiomyopathy

Treatment of chronic Chagas' disease with itraconazole and allopurinol

Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection

Reactivation of Chagas' disease during therapy of acute lymphocytic leukemia

Kidney transplantation and Chagas' disease. A two-year follow-up of a patient with parasitemia

Chagas disease and kidney transplantation

Chronic intracellular protozoan infections and kidney transplantation

Heart transplantation in patients with Chagas' disease cardiomyopathy

Pancarditis affecting the conducting system and all valves in human African trypanosomiasis

Agents of African American trypanosomiasis (sleeping sickness)

Isolated toxoplasma myocarditis in acquired immune deficiency syndrome

Lethal cardiac and cerebral toxoplasmosis in a patient with acute myeloid leukemia after successful allogeneic bone marrow transplantation

Endomyocardial biopsy in the diagnosis of toxoplasmic myocarditis

Primary and reactivated toxoplasma infection in patients with cardiac transplants. Clinical spectrum and problems in diagnosis in a defined population

Toxoplasmosis in cardiac transplantation

Cardiac echinococcosis: clinical picture and complications

Two-dimensional echocardiographic features of echinococcosis of the heart and great blood vessels. Clinical and surgical implications

Cardiac hydatid cyst with clinical features resembling subaortic stenosis

Cardiac involvement in trichinosis

Trichinosis with neurologic and cardiac involvement. Review of the literature and report of three cases

Myocarditis caused by Trichinella spiralis

Cardiac dysfunction in trichinosis

Kawasaki syndrome: clinical features. Pathophysiology, etiology and therapy

Diagnosis and management of Kawasaki disease

Kawasaki syndrome

Kawasaki syndrome-cardiovascular manifestations

Myocarditis in Kawasaki syndrome. A minor villain?

Cardiac biopsy of Kawasaki disease

Pathology of the heart in Kawasaki disease

Gallium-67 myocardial imaging for the detection of myocarditis in the acute phase of Kawasaki disease (mucocutaneous lymph node syndrome): the usefulness of single photon emission computed tomography

Myocarditis in Kawasaki disease

High-dose intravenous gammaglobulin for Kawasaki disease

Giant cell myocarditis: evidence for the macrophage origin of the giant cells

Giant cell myocarditis: an autoimmune disease?

Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11)

Isolated myocarditis versus myocardial sarcoidosis. A contribution to the discussion regarding points of resemblance between these and a report of three illustrative cases

Giant cell myocarditis: an entity distinct from sarcoidosis characterized by multiphasic myocyte destruction by cytotoxic T cells and histiocytic giant cells

A case of giant cell myocarditis and malignant thymoma: a postmortem diagnosis by needle biopsy

Orbital polymyositis and giant cell myocarditis

Severe granulomatous giant cell myocarditis in Wegener's granulomatosis

Fatal giant cell myocarditis after colectomy for ulcerative colitis

Giant cell myocarditis: monocytic immunophenotype of giant cells in a case associated with ulcerative colitis

Giant cell myocarditis associated with lymphoma: an immunocytochemical study

Complete atrioventricular block due to giant cell myocarditis

Orbital myositis, vitiligo, and giant cell myocarditis

Successful treatment of severe heart failure caused by idiopathic giant cell myocarditis

Treatment of serious heart failure by transplantation in giant cell myocarditis diagnosed by endomyocardial biopsy

Idiopathic giant cell myocarditis accompanied by asymmetric septal hypertrophy

Complete heart block due to granulomatous giant cell myocarditis: report of 3 cases

Giant cell myocarditis in a transplanted heart

Response of recurrent giant cell myocarditis in a transplanted heart to intensive immunosuppression

Giant cell myocarditis: first report of disease recurrence in the transplanted heart

Giant cell myocarditis-like appearance after transplantation: an atypical manifestation of rejection?

Endocarditis parietalis fibroplastica mit Bluteosinophilie, ein eigenartiges Krankheitsbild

The pathogenesis of endomyocardial fibrosis: the role of the eosinophil

Eosinophilia and heart disease

Acute necrotising eosinophilic myocarditis

Relation between eosinophilia and endomyocardial disease

Electron-microscopic and immunohistochemical studies on endomyocardial biopsies from a patient with eosinophilic endomyocardial disease

Toxic effects of human eosinophil products on isolated rat heart cells in vitro

Evolution to dilated cardiomyopathy from acute eosinophilic pancarditis in Churg-Strauss syndrome

Eosinophilic myocarditis associated with high-dose interleukin-2 therapy

Eosinophilic myocarditis manifesting as myocardial infarction: early diagnosis and successful treatmento

Right heart impairment in sarcoidosis: haemodynamic and echocardiographic study

Cardiac sarcoid: a clinicopathologic study of 84 unselected patients with systemic sarcoidosis

Ventricular tachycardia and ventricular aneurysm due to unrecognized sarcoidosis

Predominant myocardial sarcoidosis

Comparison of clinical features and prognosis of cardiac sarcoidosis and idiopathic dilated cardiomyopathy

Myocardial sarcoidosis

Myocardial involvement in patients with sarcoidosis. An analysis of 75 patients

Diagnosis of cardiac sarcoidosis aided by MRI

Magnetic resonance imaging as an aid to the diagnosis and treatment evaluation of suspected myocardial sarcoidosis in a fighter pilot

Sarcoidosis of the heart

Diagnostic and prognostic value of myocardial scintigraphy with thallium-201 and gallium-67 in cardiac sarcoidosis

Cardiac sarcoidosis with sudden death: treatment with the automatic implantable cardioverter defibrillator

Sarcoidosis and transplantation

Peripartum cardiomyopathy: a comprehensive review

Viral myocarditis during pregnancy: encephalomyocarditis virus infection in mice

Viral myocarditis and cardiomyopathy

Peripartum heart failure associated with prolonged tocolytic therapy

Pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation

Peripartum myocarditis and cardiomyopathy

Peripartum cardiomyopathy: clinical, hemodynamic, histologic and prognostic characteristics